WO1997038986A1 - Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors - Google Patents

Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors Download PDF

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Publication number
WO1997038986A1
WO1997038986A1 PCT/US1997/005497 US9705497W WO9738986A1 WO 1997038986 A1 WO1997038986 A1 WO 1997038986A1 US 9705497 W US9705497 W US 9705497W WO 9738986 A1 WO9738986 A1 WO 9738986A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
sulfonyl
methyl
phenylisoxazol
acetamide
Prior art date
Application number
PCT/US1997/005497
Other languages
English (en)
French (fr)
Inventor
John J. Talley
James W. Malecha
Stephen Bertenshaw
Matthew J. Graneto
Jeffery S. Carter
Jinglin Li
Srinivasan Nagarajan
David L. Brown
Donald J. Rogier, Jr.
Thomas D. Penning
Ish K. Khanna
Xiangdong Xu
Richard M. Weier
Original Assignee
G.D. Searle & Co.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to SK1242-98A priority Critical patent/SK285353B6/sk
Priority to JP53713997A priority patent/JP3382624B2/ja
Priority to BR9708574A priority patent/BR9708574A/pt
Priority to EA199800919A priority patent/EA003319B1/ru
Priority to MEP-1998-443A priority patent/ME00768B/me
Priority to HU9901807A priority patent/HU225473B1/hu
Priority to APAP/P/1998/001355A priority patent/AP1009A/en
Priority to IL12584997A priority patent/IL125849A/xx
Priority to DK02025005T priority patent/DK1288206T3/da
Priority to AT97921092T priority patent/ATE233743T1/de
Priority to SI9720101A priority patent/SI22713B/sl
Priority to CA002249009A priority patent/CA2249009C/en
Priority to DE69719496T priority patent/DE69719496T2/de
Priority to SI9720035A priority patent/SI9720035B/sl
Priority to NZ331542A priority patent/NZ331542A/xx
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Priority to PL97329276A priority patent/PL195955B1/pl
Priority to DK97921092T priority patent/DK0892791T3/da
Priority to RO98-01469A priority patent/RO121338B1/ro
Priority to EE9800351A priority patent/EE03685B1/xx
Priority to EP97921092A priority patent/EP0892791B1/en
Priority to AU27227/97A priority patent/AU734275C/en
Priority to HK99104900.3A priority patent/HK1019741B/xx
Publication of WO1997038986A1 publication Critical patent/WO1997038986A1/en
Priority to UA98115994A priority patent/UA47475C2/uk
Priority to IS4863A priority patent/IS2156B/is
Priority to NO19984727A priority patent/NO314184B1/no
Priority to LVP-98-215A priority patent/LV12239B/en
Priority to IS7292A priority patent/IS7292A/is
Priority to US10/939,852 priority patent/US7420061B2/en

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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/16—Amides, e.g. hydroxamic acids
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • cyclooxygenase-2 (COX-2) provides a viable target of
  • prodrugs of antiinflammatory compounds are advantageous, especially where the prodrugs have increased water solubility or delayed onset of action.
  • JP 5,323,522 describes the use of heterocyclic compounds in black and white photographic material.
  • U.S. Patent No. 5,389,635 describes substituted imidazoles as angiotensin II antagonists.
  • U.S. Patent No. 5,387,592 describes substituted benzimidazole derivatives as angiotensin II antagonists.
  • G. Dorofeenko et al [Khim . Farm. Zh . , 16, 920 (1982)] describe pyridinium salts as antiviral agents.
  • U.S. Patent No. 5,338,749 describes diaryl- substituted heterocyclyl compounds as antiarthritis agents.
  • W094/26731 describes thiophene compounds which selectively inhibit cyclooxygenase-2.
  • WO95/00501 describes compounds which selectively inhibit
  • a class of substituted sulfonamide compounds useful as prodrugs is defined by Formula I :
  • A is a ring substituent selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalky, carboxyalkoxyalkyl,
  • cycloalkylalkyl alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl,
  • alkylthioalkyl arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N- arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino, N- aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N- arylamino, aminoalkyl, alkylaminoalkyl, N- arylaminoalkyl, N-aralkylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N- arylamin
  • R 1 is selected from heterocyclyl
  • radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
  • R 2 is selected from hydrido and
  • R 3 is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl,
  • alkoxycarbonylalkylcarbonyl alkoxycarbonylcarbonyl, amino acid residue, and
  • A is not tetrazolium, or pyridinium; and further provided A is not indanone when R 3 is alkyl or carboxyalkyl;
  • Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other cyclooxygenase-2 mediated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the
  • compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis,
  • spondyloarthropathies gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • Such compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, skin-related conditions such as psoriasis, eczema, burns and
  • Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and
  • Compounds of the invention would be useful for the prevention or treatment of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin.
  • Compounds of the invention would be useful in treating inflammation m such diseases as vascular diseases, migraine headacnes, periarteritis nodosa, thyroiditis, aplastic anemia,
  • sarcoidosis multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensltivity, swelling occurring after injury, myocardial ischemia, and the like.
  • the compounds would also be useful in the treatment of ophthalmic diseases, such as retmitis, retmopathies, uveitis, ocular
  • the compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis.
  • the compounds would also be useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer's disease, and central nervous system damage resulting from stroke, ischemia and trauma.
  • the compounds of the invention are useful as anti- mflammatory agents, such as for the treatment of arthritis, with the additional benefit of having
  • These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis.
  • the compounds would also be useful in the treatment of pam, but not limited to postoperative pain, dental pam, muscular pam, and pam resulting from cancer.
  • the compounds would be useful for the prevention of dementias, such as Alzheimer's disease.
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the present compounds may also be used in co- therapies, partially or completely, in place of other conventional antimflammatories, such as together with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB 4 antagonists and LTA 4 hydrolase inhibitors .
  • Suitable LTB 4 inhibitors include, among others, ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS- 25019C, Leo Denmark compound ETH-615, Lilly compound LY- 293111, Ono compound ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024, 264086 and 292728, ONO compound ONO-LB457 , Searle compound SC-53228,
  • the LTB 4 inhibitors are selected from ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS- 25019C, Leo Denmark compound ETH-615, Lilly compound LY- 293111, Ono compound ONO-4057, and Terumo compound TMK- 688.
  • Suitable 5-LO inhibitors include, among others, masoprocol, tenidap, zileuton, pranlukast, tepoxalm, ⁇ lopirox, flezelastine hydrochloride, enazadrem
  • the present compounds may also be used in any combination.
  • combination therapies with opioids and other analgesics such as morphine, meperidine or codeine.
  • cyclooxygenase-2 inhibitor embraces compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
  • the compounds have a cyclooxygenase-2 IC 50 of less than about 0.5 ⁇ M, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100.
  • the compounds have a cyclooxygenase-1 IC 50 of greater than about 1 ⁇ M, and more preferably of greater than 20 ⁇ M.
  • Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-mduced side
  • phrase "combination therapy" in defining use of a cyclooxygenase-2 inhibitor agent and another agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multnple, separate capsules for each agent.
  • prodrug refers to compounds which are drug precursors which, following administration to a subject and subsequent absorption, is converted to an active species m vivo via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body. More preferred prodrugs produce products from the conversion process which are generally accepted as safe.
  • cyclooxygenase-2 consists of compounds of Formula I wherein A is selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, lower cycloalkenyl and phenyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from formyl, lower alkylcarbonyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower haloalkylsulfonyloxy, lower alkoxyalkyloxyalkyl, lower carboxyalkoxyalkyl, lower cycloalkylalkyl, lower alkenyl, lower alkynyl,
  • heterocyclyloxy lower alkylthio, lower cycloalkyl, phenyl, 5-6 membered heterocyclyl, lower cycloalkenyl, lower phenylalkyl, 5-6 membered heterocyclylalkyl, lower
  • alkylthioalkyl phenylcarbonyl, lower phenylalkylcarbonyl, lower phenylalkenyl, lower alkoxyalkyl, lower
  • alkoxyalkylcarbonyl (5-6-membered heteroaryl) carbonyl, lower alkoxycarbonylalkylcarbonyl, lower
  • a more preferred class of compounds whicn inhibit cyclooxygenase-2 consists of compounds of Formula I wherein A is a radical selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl,
  • R 1 is selected from thienyl, oxazolyl, isoxazolyl, furyl, thiazolyl, pyridyl, and phenyl, where R 1 is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio; wherein R 2 is hydrido, or ethoxycarbonylmethyl; and wherein R 1 is selected from methyl, carboxymethyl, formyl,
  • methoxycarbonylmethylcarbonyl aminomethylcarbonyl, methoxycarbonylethylcarbonyl, methoxycarbonylcarbonyl, tert-butoxycarbonylaminomethylcarbonyl, and
  • A is a ring substituent selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, lower cycloalkenyl and phenyl; wherein A is optionally substituted at a substitutable position with one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro,
  • alkoxycarbonyl lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower alkylcarbonyloxyalkyl, and phenyl;
  • R 4 is selected from heterocyclyl
  • R 4 is optionally substituted at a substitutable position with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; and
  • R 5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower
  • alkoxycarbonyl lower aminoalkyl
  • alkoxycarbonylaminoalkyl and lower
  • a preferred class of compounds consists of those compounds of Formula II wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, mdenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyciopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkylcarbonyloxyalkyl, phenyl and
  • alkylsulfinyl halo, lower alkoxy and lower alkylthio; and wherein R 5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower
  • alkoxycarbonylalkyl lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl; or a pharmaceutically- acceptable salt thereof.
  • a class of compounds of particular interest consists of those compounds of Formula II wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl,
  • R 4 is selected from thienyl, pyridyl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio; and wherein R 5 is selected from hydrido, methyl, ethyl, isopropyl, propyl, tert-butyl, butyl, pentyl, methoxy, tert-butoxy, methoxyethyl, ethoxymethyl, methoxymethyl, phenyl, carboxyethyl, methoxycarbonylmethyl,
  • R 1 is selected from hydroxyl, lower alkyl, carboxyl, halo, lower carboxyalkyl, lower
  • alkoxycarbonylalkyl lower aralkyl, lower alkoxyalkyl, lower alkoxyalkyloxyalkyl, lower aralkoxyalkyl, lower haloalkyl, lower hydroxylalkyl, lower
  • R 7 is one or more radicals selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; and
  • R 8 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower
  • alkoxycarbonyl lower aminoalkyl
  • alkoxycarbonylaminoalkyl and lower
  • a preferred class of compounds consists of those compounds of Formula III wherein R 6 is selected from lower alkyl, lower haloalkyl, and lower hydroxylalkyl; wherein R 7 is one or more radicals selected from hydrido, lower alkyl, halo, and lower alkoxy; and wherein R 8 is selected from lower alkyl, phenyl, and lower aminoalkyl; or a pharmaceutically-acceptable salt thereof.
  • a more preferred class of compounds consists of those compounds of Formula III wherein R 6 is selected from methyl, difluoromethyl and hydroxymethyl; wherein R 7 is one or more radicals selected from hydrido, methyl, fluoro, chloro, bromo, and methoxy; and wherein R 8 is selected from methyl, ethyl, isopropyl, propyl, tert-butyl, butyl, pentyl, phenyl, and aminomethyl; or a pharmaceutically-acceptable salt thereof.
  • a family of specific compounds of particular interest within Formulas I-III consists of compounds and pharmaceutically-acceptable salts thereof as follows:
  • Formulas I-III consists of compounds as follows: N-[[4-[2-(2-methylpyridin-6-yl)-4-(trifluoromethyl)-1H- imidazol-1-yl]phenyl]sulfonyl]acetamide, sodium salt;
  • hydro denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH 2 -) radical. Where used, either alone or withm other terms such as "haloalkyl",
  • alkylsulfonyl "alkoxyalkyl” and “hydroxyalkyl”
  • alkyl embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals havmg one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms . Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.
  • the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals havmg one to about
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl .
  • alkynyl denotes linear or branched radicals having at least one carbon-carbon triple bond, and having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms.
  • alkynyl radicals are "lower alkynyl” radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • cycloalkyl is cycloalkyl
  • cycloalkyl radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and
  • cyclohexyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include
  • halo means halogens such as fluorine, chlorine, bromine or iodine.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl,
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred
  • hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include
  • alkoxy and alkyloxy embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms . Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • the "alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred haloalkoxy radicals are "lower
  • haloalkoxy radicals having one to six carbon atoms and one or more halo radicals.
  • examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.
  • substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.
  • heterocyclyl embraces saturated,
  • saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidmyl, piperidino, piperazinyl, etc.);
  • heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • Heterocyclyl radiclas may include a pentavalent nitrogen, such as in tetrazolium and
  • heteroaryl embraces unsaturated heterocyclyl radicals.
  • heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolmyl, imidazolyl,
  • pyrazolyl pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.
  • unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms for example, mdolyl, isoindolyl, mdolizinyl, benzimidazolyl, qumolyl, isoquinolyl, mdazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,
  • unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom for example, thienyl, etc.
  • unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl, etc.) etc.
  • heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzoxazolyl, benzoxadiazolyl, etc.
  • unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazoiyl, 1,2,5- thiadiazolyl, etc.) etc.
  • heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., benzothiazolyl
  • heteroaryl also embraces radicals where heterocyclyl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran,
  • heterocyclyl group may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.
  • alkylthioalkyl embraces radicals containing an
  • alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are
  • lower alkylthioalkyl radicals having alkyl radicals of one to six carbon atoms.
  • lower alkylthioalkyl radicals include methylthiomethyl.
  • sulfonyl whether used alone or linked to other terms such as “alkylsulfonyl”, denotes a divalent radical, -SO 2 -.
  • Alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
  • the "alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.
  • sulfamyl denotes NH 2 O 2 S-.
  • acyl denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals.
  • alkanoyl radicals examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartarie, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, ⁇ -hydroxybutyric, galactaric and galacturonic acids.
  • aroyl embraces aryl radicals with a carbonyl radical as defined below.
  • aroyl examples include benzoyl, naphthoyl, phenylacetyl, and the like, and the aryl in said aroyl may be additionally substituted, such as in p-hydroxybenzoyl, and salicylyl.
  • carbonyl whether used alone or with other terms, such as
  • carboxyalkyl denotes -CO 2 H.
  • Carboxyalkyl embraces alkyl radicals substituted with a carboxy radical. More preferred are "lower
  • carboxyalkyl which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo.
  • lower carboxyalkyl radicals include carboxymethyl
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
  • alkylcarbonyl examples include radicals having alkyl, hydroxylalkyl, aryl, arylalkyl and aryl-hydroxylalkyl radicals, as defined herein, attached to a carbonyl radical.
  • examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl,
  • Carboxyalkylcarbonyl embraces alkylcarbonyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkylcarbonyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with hydroxyl.
  • Examples of such lower carboxyalkylcarbonyl radicals include carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, HO 2 C(CHOH) 4 C(O)-, HO 2 C(CHOH) 2 C(O) - , HO 2 C(CH 2 )(CHOH)C(O)-, and HO 2 CCH 2 C(OH)(CO 2 H)C(O)-.
  • the term "carboxyalkenylcarbonyl” embraces derivatives of maleic and fumaric acids. Examples of such
  • carboxyalkenylcarbonyl radicals include (Z)- carboxyethenylcarbonyl and (E)-carboxyethenylcarbonyl.
  • aralkyl embraces aryl-s bstituted alkyl radicals such as benzyl, diphenylmethyl,
  • triphenylmethyl, phenylethyl, and diphenylethyl triphenylmethyl, phenylethyl, and diphenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • heterocyclylalkyl embraces saturated and partially unsaturated heterocyclyl-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroaryl- substituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and
  • the heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • aryloxy embraces aryl radicals attached through an oxygen atom to other radicals.
  • arylthio embraces aryl radicals attached to a sulfur atom.
  • aralkoxy embraces aralkyl radicals attached through an oxygen atom to other radicals.
  • heterocyclyloxy embraces heterocyclyl radicals attached through an oxygen atom to other radicals.
  • aralkoxyalkyl embraces aralkoxy radicals attached through an oxygen atom to an alkyl radical.
  • aralkylthio embraces aralkyl radicals attached to a sulfur atom.
  • aralkylthioalkyl embraces aralkylthio radicals
  • aminoalkyl embraces alkyl radicals substituted with amino radicals. More preferred are "lower
  • aminoalkyl radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • alkylamino denotes amino groups which are substituted with one or two alkyl radicals. Preferred are “lower alkylamino" radicals having alkyl porions having one to six carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N- alkylamino, such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino or the like.
  • arylamino denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino. The "arylamino" radicals may be further substituted on the aryl ring portion of the radical.
  • aminoalkylamino embraces amino groups which are
  • N-arylaminoalkyl and “N-aryl-N-alkyl-aminoalkyl” denote aminoalkyl groups which are substituted with one aryl radical or one aryl and one alkyl radical,
  • Examples of such radicals include N- phenylaminomethyl and N-phenyl-N-methylaminomethyl .
  • the term “alkylaminocarbonyl” denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” and “lower N,N- dialkylaminocarbonyl” radicals with lower alkyl portions as defined above.
  • alkylaminoalkyl embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
  • aryloxyalkyl embraces radicals having an aryl radicals attached to an alkyl radical through a divalent oxygen atom.
  • arylthioalkyl embraces radicals having an aryl
  • Amino acid residue means any of the naturally occurring alpha-, beta- and gamma-amino carboxylic acids, including their D and L optical isomers and racemic mixtures thereof, synthetic amino acids, and derivatives of these natural and synthetic amino acids .
  • the amino acid residue is bonded either through an amino or an acid functional group of the amino acid.
  • the naturally occurring amino acids which can be incorporated in the present invention include, but are not limited to, alanme, arginine, asparagme, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidme, isoleucine, leucme, lysine, methionme, ornithine, phenylalanme, proline, serine, threonine, cyclohexylalanme, tryptophan, tyrosine, valme, ⁇ -alanme, and ⁇ -aminobutyric acid.
  • Derivatives of amino acids which can be incorporated in the present invention include, but are not limited to amino acids having protected and modified carboxylic acids,
  • the present invention comprises a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
  • the present invention also comprises a method of
  • A is a ring substituent selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from
  • alkylcarbonyl formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, arylthioalkyl, arylcarbonyl,
  • alkylaminosulfonyl N-arylaminosulfonyl, arylsulfonyl, and N- alkyl-N-arylaminosulfonyl; wherein R 1 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R 1 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl,
  • alkylcarbonylaminoalkylcarbonyl or a pharmaceutically- acceptable salt thereof.
  • the method of the present invention also includes prophylactic treatment.
  • a preferred method of the invention is the administration of water soluble compounds of Formulas I-III via injection.
  • Stereoisomers thereof are also included in the family of compounds of Formula I.
  • Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof. Accordingly, some of the compounds of this
  • optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of
  • diastereoisomeric salts by treatment with an optically active acid or base.
  • appropriate acids are tartarie, diacetyltartaric, dibenzoyltarta ⁇ c, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting an amine functionality of precursors to compounds of Formula I with an optically pure acid in an activated form or an optically pure isocyanate.
  • diastereomeric derivatives can be prepared by reacting a carboxyl functionality of precursors to compounds of Formula I with an optically pure amine base.
  • synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the
  • compounds of Formula I can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic,
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts and organic salts. More preferrred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group Ila) salts and other
  • Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Preferred organic salts can be made from tertiary amines and quanternary ammonium salts, including in part, trometamine, diethylamine, N,N'-dibenzylethylenediamme, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the
  • cyclooxygenase-2 inhibitor prodrugs of the invention can be synthesized according to the following procedures of Schemes I-XVII, wherein the R 1 -R 8 substituents are as defined for Formulas I-III, above, except where further noted.
  • step 1 ketone 1 is treated with a base, preferably NaOMe or NaH, and an ester, or ester equivalent, to form the intermediate diketone 2 (in the enol form) which is used without further purification.
  • step 2 diketone 2 in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the hydrochloride salt or the free base of a substituted hydrazine at reflux to afford a mixture of pyrazoles 3 and 4. Recrystallization or chromatography affords 3 usually as a solid. Similar pyrazoles can be prepared by methods
  • Scheme II shows the four step procedure for forming cyclooxygenase-2 inhibitor pyrazoles 8 as described in U.S. patent No. 5,486,534 (where R a is hydrido or alkyl) from ketones 5.
  • ketone 5 is reacted with a base, such as lithium bis (trimethylsilyl) amide or lithium
  • step 2 the anion is reacted with an acetylatmg reagent to provide diketone 6.
  • step 3 the reaction of diketone 6 with hydrazine or a substituted hydrazine, gives pyrazole 7.
  • step 4 the pyrazole 7 is oxidized with an oxidizing reagent, such as Oxone ® (potassium peroxymonosulfate), 3- chloroperbenzoic acid (MCPBA) or hydrogen peroxide, to give a mixture of the desired 3-(alkylsulfonyl)phenyl-pyrazole 8 and the 5-(alkylsulfonyl)phenyl-pyrazole isomer.
  • Oxone ® potassium peroxymonosulfate
  • MCPBA 3- chloroperbenzoic acid
  • Sulfonamides 9 can be prepared such as by the Huang method [Tet. Lett., 35, 7201-04 (1994)] .
  • diketone 6 can be formed from ketone 5 by treatment with a base, such as sodium hydride, in a solvent, such as dimethylformamide, and further reacting with a nitrile to form an aminoketone. Treatment of the aminoketone with acid forms the diketone 6.
  • a base such as sodium hydride
  • a solvent such as dimethylformamide
  • Treatment of the aminoketone with acid forms the diketone 6.
  • Similar pyrazoles can be prepared by methods described in U.S. Pat. No. 3,984,431 which is incorporated by reference.
  • thiophenes (where T is S, and R b is alkyl) can be prepared by the methods described in U.S. Patent Nos. 4,427,693, 4,302,461, 4,381,311, 4,590,205, and 4,820,827, and PCT documents WO 95/00501 and W094/15932, which are
  • Cyclooxygenase-2 inhibitor diaryl/heteroaryl oxazoles can be prepared by the methods described in U.S. Patent Nos. 5,380,738, 3,743,656, 3,644,499 and 3,647,858, and PCT documents WO 95/00501 and WO94/27980, which are
  • isoxazoles can be prepared by the methods described in PCT application Serial No. US96/01869, PCT documents
  • Sulfonamides 27 can be formed from the hydrated isoxazole 26 in a two step procedure. First, hydrated isoxazole 26 is treated at about 0 °C with two or three equivalents of chlorosulfonic acid to form the corresponding sulfonyl chloride. In step two, the sulfonyl chloride thus formed is treated with concentrated ammonia to provide the sulfonamide derivative 27.
  • Scheme VI shows a three step preparation of the cyclooxygenase-2 inhibitor imidazoles 33.
  • step 1 the reaction of substituted nitriles (R 1 CN) 28 with primary phenylamines 29 in the presence of alkylaluminum reagents such as trimethylaluminum, triethylaluminum,
  • step 2 the reaction of amidine 30 with 2-haloketones (where X is Br or Cl) in the presence of bases, such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or hindered tertiary amines such as N, N' - dnsopropylethylamine, gives the 4 , 5-dihydroimidazoles 31 (where R" is alkyl).
  • bases such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or hindered tertiary amines such as N, N' - dnsopropylethylamine.
  • step 3 the 4, 5-dihydroimidazoles 31 may be dehydrated in the presence of an acid catalyst such as 4-toluenesulfonic acid or mineral acids to form the 1,2- disubstituted imidazoles 32 of the invention.
  • an acid catalyst such as 4-toluenesulfonic acid or mineral acids
  • Suitable solvents for this dehydration step are e.g., toluene, xylene and benzene.
  • Trifluoroacetic acid can be used as solvent and catalyst for this dehydration step.
  • Sulfonamides 33 can be prepared such as by the Huang method [Tet. Lett., 35, 7201-04 (1994)].
  • the intermediate 31 may not be readily isolable.
  • the reaction proceeds to give the targeted imidazoles directly.
  • imidazoles can be prepared having the sulfonylphenyl moiety attached at position 2 and R 1 attached at the nitrogen atom at position 1.
  • Diaryl/heteroaryl imidazoles can be prepared by the methods described in U.S. Patent ⁇ os. 4,822,805 and PCT documents WO 93/14082 and WO96/03388, which are incorporated by reference.
  • Imidazole cyclooxygenase-2 inhibitor compounds 41 may be synthesized according to the sequence outlined in Scheme VII. Aldehyde 34 may be converted to the protected
  • cyanohydrin 35 by reaction with a trialkylsilyl cyanide, such as trimethylsilyl cyanide (TMSCN) in the presence of a catalyst such as zinc iodide (Znl 2 ) or potassium cyanide (KCN).
  • TMSCN trimethylsilyl cyanide
  • Znl 2 zinc iodide
  • KCN potassium cyanide
  • Reaction of cyanohydrin 35 with a strong base followed by treatment with benzaldehyde 36 and using both acid and base treatments, in that order, on workup gives benzoin 37.
  • strong bases suitable for this reaction are lithium diisopropylamide (LDA) and lithium hexamethyldisilazane.
  • Benzoin 37 may be converted to benzil 38 by reaction with a suitable oxidizing agent, such as bismuth oxide or manganese dioxide, or by a Swern oxidation using dimethyl sulfoxide (DMSO) and
  • Benzil 38 may be obtained directly by reaction of the anion of cyanohydrin 35 with a substituted benzoic acid halide. Any of compounds 37 and 38 may be used as intermediates for conversion to
  • oxidation of the sulfide to the sulfone may be carried out at any point along the way beginning with compounds 36, and including oxidation of imidazoles 39, using, for examples, reagents such as hydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid (MCPBA) and potassium peroxymonosulfate (OXONE ® ).
  • Sulfonamides 41 can be prepared such as by the Huang method [Tet. Lett., 35, 7201-04 (1994)].
  • Diaryl/heteroaryl imidazoles can be prepared by the methods described in U.S. Patent Nos.
  • Diaryl/heteroaryl cyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent No. 5,344,991, and PCT document WO 95/00501, which are incorporated by reference.
  • Synthetic Scheme IX shows the procedure for the preparation of 1, 2-diarylbenzene cyclooxygenase-2 inhibitor agents 51 from 2-bromo-biphenyl intermediates 49 (prepared similar to that described in Synthetic Scheme VIII) and the appropriate substituted phenylboromc acids. Using a coupling procedure similar to the one developed by Suzuki et al. [Synth. Commun . , 11, 513 (1981)],
  • intermediates 49 are reacted with the boronic acids in toluene/ethanol at reflux in the presence of a Pd°
  • Sulfonamides 51 can be prepared such as by the Huang method [Tet. Lett . , 35, 7201-04 (1994)].
  • Such terphenyl compounds can be prepared by the methods described in U.S. application Serial No. 08/346,433, which is incorporated by reference.
  • Diaryl/heteroaryl thiazole cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent No. 4,051,250, 4,632,930, European document EP 592,664, and PCT documents WO96/03392, and WO 95/00501, which are
  • Isothiazoles can be prepared as described in PCT document WO 95/00501.
  • Diaryl/heteroaryl pyridine cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent Nos. 5,169,857, 4,011,328, 4,533,666, PCT application Serial No. US96/01110 and PCT application Serial No.
  • Synthetic Scheme XI illustrates a method for the preparation of acylated sulfonamides 57.
  • the method involves treatment of an unsubstituted sulfonamide 56 with a suitable acylating agent such as an anhydride, acid chloride, acyl imidazole, or active ester, in the presence of base and a suitable solvent, such as tetrahydrofuran (THF), to afford the acylated
  • the product 57 can then be isolated by chromatography or by crystallization.
  • Synthetic Scheme XII shows the method for the preparation of the corresponding salt form of 57.
  • a suitable strong base such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like produces the corresponding salt form 58.
  • a suitable strong base such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • solvents such solvents as ethanol and tetrahydrofuran are preferred.
  • Synthetic Scheme XIII shows the method used for the preparation of substituted sulfonamides 60.
  • the step involves treatment of a suitable sulfonyl chloride 59 with an amine to produce the substituted sulfonamide 59.
  • the amine may be either a primary amine (R 1 NH 2 ) or a secondary amine (R 3 R 2 NH).
  • the reaction is generally conducted in the presence of added base.
  • the reaction may also be conducted in the presence of excess amine. Under the conditions of excess amine, the amine functions as both nucleophile and base.
  • Synthetic Scheme XIV shows the method used for the synthesis of N-substituted acyl sulfonamides 61, The procedure involves treatment of the salt of an acylated sulfonamide 58 with an alkyl halide (R 2 -X) to produce the corresponding N-alkylated acyl
  • This process may be conducted in a
  • Synthetic Scheme XV illustrates the method used for the synthesis of certain N-acylated sulfonamides 57.
  • the procedure involves treatment of the sulfonamide 56 with an excess of an anhydride, acid chloride or carbamyl chloride in the presence of a tertiary amine base to provide the
  • Oxidation with pyridinium chlorochromate produces the ketones 68.
  • Condensation with a [(N- substituted amino)sulfonyl]benzeneamine in the presence of p-toluenesulfonic acid (produces the substituted pyrrole sulfonamide 69.
  • Synthetic Scheme XVII illustrates the method for the preparation of acylated isoxazole sulfonamides 71.
  • the step involves treatment of an unsubstituted sulfonamide 70 with a suitable acylating agent such as an anhydride, acid chloride, acyl imidazole, or active ester to afford the acylated sulfonamide 71.
  • a suitable acylating agent such as an anhydride, acid chloride, acyl imidazole, or active ester to afford the acylated sulfonamide 71.
  • the product 71 can be isolated by chromatography or by crystallization.
  • Acetic anhydride (1.01 g, 9.39 mmol) and triethylamine (0.401 g, 3.97 mmol) were added to a solution of 4-[5-methyl- 3-(3-fluorophenyl)isoxazol-4-yl]benzenesulfonamide (1.10 g, 3.31 mmol) and N,N-dimethylpyridine (0.202 g) in dry
  • 1 H NMR (D 2 O/300 MHz) 7.62 (d, 2H, J 8.4 Hz), 7.2 (m, 7H), 2.27 (s, 3H), 1.77 (s, 3H).
  • Example 73 (0.867 g, 2.09 mmol) in methanol was treated with sodium hydroxide. The reaction was concentrated in vacuo , dissolved in water and slowly acidified with 1 N HCl to yield a solid.
  • Step 2 Preparation of N-[[4-(5-hydroxymethyl-3- phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide
  • Step 1 4-yl]phenyl]sulfonyl]propanamide (Step 1) was dissolved in methanol and NaOH solution (0.89 mL of 2.5 N, 2.24 mmol) added with stirring. After
  • Step 3 Preparation of N-[[4-(5-hydroxymethyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide, sodium salt
  • the 5,5-dimethyl-1,3-dioxane-2-propanol was synthesized by following the literature procedure (J. Org. Chem . 57, 2195,1992).
  • Step 3 Preparation of C: ⁇ -(4-fluorophenyl) -5,5- dimethyl-1,3-dioxane-2-propanol
  • Step 4 Preparation of 3-(5,5-dimethyl-1,3-dioxan-2- yl)-1-(4-fluorophenyl)propan-1-one
  • Step 3 To a solution of ⁇ -(4-fluorophenyl)-5,5-dimethyl- 1,3-dioxane-2-propanol (Step 3) (2.6 g, 10.7 mmol) in methylene chloride (100 ml), pyridinium chlorochromate (3.5 g, 16.05 mmol) was added. After stirring at room temperature for 3 hr, the reaction mixture was diluted with ether and filtered through a short silica gel column.
  • Step 5 N-methyl-4- nitrobenzenesulfonamide (Step 5) (4.8 g, 22.2 mmol) in methanol (100 ml) in a Parr bottle was added Raney- nickel in methanol. The reaction mixture was flushed with nitrogen and hydrogen several times and maintained under hydrogen at delivery pressure of 5 psi. After stirring at 25 °C for approximately 20 hr, the reaction was vented and purged with nitrogen. The contents of the reaction were filtered and concentrated to remove the solvent. The 4-[(N-methylamino)sulfonyl]aniline obtained as a white solid (4.1 g, 100%) was used in the next step without further purification: mp (DSC) 138 °C.
  • Step 4 A mixture of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1- (4-fluorophenyl)propan-1-one (Step 4) (400 mg, 1.5 mmol), 4-[(N-methylamino)sulfonyl]aniline (Step 6) (308 mg, 1.65 mmol) and p-toluenesulfonic acid (40 mg) in toluene (80 ml) was heated to reflux for 48 hr. The reaction mixture was cooled, filtered and concentrated.
  • Step 1 Preparation of N-acetyl-N-[[4-(5-methyl-3- phenylisoxazol-4-vl)phenyl]sulfonvn ⁇ rvcine, ethyl ester
  • Step 1 (0.24 g, 0.54 mmol) in methanol was added
  • Step 1 To 20 mL of stirring chlorosulfonic acid cooled to -5 °C was added 3 ,4-diphenyl-2-( 5H ) - furanone (Step 1) (3.160 g, 13.4 mmol) portion- wise over 30 minutes. The solution was warmed to room temperature and maintained at that
  • a composition is prepared having the following components: N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl] sulfonyl]propanamide, sodium salt 40 mg phosphate buffer, pH 7.5 (10 mM) 2 ml mannitol 40 mg
  • Mannitol (40 mg) is added to phosphate buffer solution (2 ml).
  • phosphate buffer solution (2 ml).
  • the N-[[4-(5-methyl-3- phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide, sodium salt is added and the resulting solution is lyophilized.
  • the carrageenan foot edema test was performed with materials, reagents and procedures essentially as described by Winter, et al., (Proc. Soc . Exp . Biol . Med. , Ill, 544 (1962)).
  • Male Sprague-Dawley rats were selected in each group so that the average body weight was as close as possible. Rats were fasted with free access to water for over sixteen hours prior to the test. The rats were dosed orally (1 mL) with compounds suspended in vehicle
  • the conversion of the prodrugs by S9 liver fractions was determined by the following method.
  • the S9 liver fraction suspension (HAM) was thawed and the suspension was stirred by vortex.
  • the suspension was mixed with 12M urea at 1:7, v:v, (yielding 10.5 M urea final concentration) and further stirred by vortex.
  • the S9 suspension solution was partially purified by solid phase extraction (Vac-Elut apparatus:C 18 columns (Varian #1210- 2001)) eluting with acetonitrile.
  • the fractions were mixed by vortex and concentrated to dryness under nitrogen (no heat).
  • the fractions were resuspended in 100 ⁇ l acetonitrile: phosphate buffer (8.3 mM, pH 7.2) (20:80).
  • the compounds were dissolved in water (0.2 ml, 10 ug/ml) and incubated at 37 °C (pH 7.2, 90
  • compositions comprising the active
  • carrier materials
  • active compounds of this combination therapy in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier” materials) and, if desired, other active ingredients.
  • carrier materials
  • active compounds of the present invention may be administered by any suitable route, preferably in the form of a
  • composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and composition may, for example, be administered orally, mtravascularly (IV),
  • IM intramuscularly
  • the pharmaceutically acceptable salt for oral administration, the pharmaceutical
  • composition may be in the form of, for example, a tablet, hard or soft capsule, lozenges, dispensable powders, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.
  • the active ingredient may also be administered by injection (IV, IM, subcutaneous or jet) as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier.
  • IV injection
  • IM subcutaneous or jet
  • the pH of the composition may be adjusted, if necessary, with suitable acid, base, or buffer.
  • suitable bulking, dispersing, wetting or suspending agents, including mannitol and PEG 400 may also be included in the composition.
  • parenteral composition can also include a compound formulated as a sterile solid substance, including lyophilized powder, in injection vials. Aqueous solution can be added to dissolve the compound prior to injection.
  • the amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the inflammation or
  • the prodrug compositions should include similar dosages as for the parent compounds.
  • the pharmaceutical compositions may contain active
  • ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 0.5 to 250 mg and most preferably between about 1 and 60 mg.
  • the daily dose can be administered in one to four doses per day.
  • the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w,
  • the active When formulated in an ointment, the active
  • ingredients may be employed with either paraffmic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in- water cream base.
  • the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
  • the topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal
  • penetration enhancers include dimethylsulfoxide and related analogs.
  • the compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or
  • microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an
  • emulsifier it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
  • the cream should preferably be a non-greasy, non-stainmg and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone orin combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients.
  • suitable carrier especially an aqueous solvent for the active ingredients.
  • the antimflammatory active ingredients are preferably present in such formulations in a
  • the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium algmate,
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous lsotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

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PCT/US1997/005497 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors WO1997038986A1 (en)

Priority Applications (28)

Application Number Priority Date Filing Date Title
NZ331542A NZ331542A (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors and salts thereof that are useful in treating inflammation and inflammation-related disorders
BR9708574A BR9708574A (pt) 1996-04-12 1997-04-11 Derivados benzeno sulfonamida substituídos como pródrogas de inibidores cox-2
EA199800919A EA003319B1 (ru) 1996-04-12 1997-04-11 Производные замещенного бензолсульфонамида - пролекарства ингибиторов cox-2
MEP-1998-443A ME00768B (me) 1996-04-12 1997-04-11 Derivati supstituisanih benzol sulfonamida kao pro-lekovi cox-2 inhibitora
HU9901807A HU225473B1 (en) 1996-04-12 1997-04-11 Heterocycle substituted n-acyl benzenesulfonamide derivatives, process for their preparation and their use as prodrug for the preparation of pharmaceutical compositions treating inflammation or inflammation-associated disorders
APAP/P/1998/001355A AP1009A (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as products of COX-2 inhibitors.
IL12584997A IL125849A (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives, their preparation and pharmaceutical compositions comprising them
DK02025005T DK1288206T3 (da) 1996-04-12 1997-04-11 Substituerede benzensulfonamidderivater som prolægemidler af COX-2-inhibitorer
AT97921092T ATE233743T1 (de) 1996-04-12 1997-04-11 N-((4-(5-methyl-3-phenylisoxazol-4- yl)phenyl)sulphonylpropylamid und sein natriumsalz als pro-pharmakon von cox-2 inhibitoren
SI9720101A SI22713B (sl) 1996-04-12 1997-04-11 Substituirani benzensulfonamidni derivati kot predzdravila COX-2 inhibitorjev
CA002249009A CA2249009C (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors
DE69719496T DE69719496T2 (de) 1996-04-12 1997-04-11 N-[[4-(5-METHYL-3-PHENYLISOXAZOL-4-YL]PHENYL]SULPHONYLPROPYLAMID und sein NATRIUMSALZ ALS PRO-PHARMAKON VON COX-2 INHIBITOREN
SI9720035A SI9720035B (sl) 1996-04-12 1997-04-11 Substituirani benzensulfonamidni derivati kot predzdravila COX-2 inhibitorjev
SK1242-98A SK285353B6 (sk) 1996-04-12 1997-04-11 Substituované benzénsulfónamidy ako proliečivá COX-2 inhibítorov, farmaceutická kompozícia a spôsobich prípravy a použitia
EP97921092A EP0892791B1 (en) 1996-04-12 1997-04-11 N-[[4-(5-METHYL-3-PHENYLISOXAZOL-4-YL]PHENYL]SULFONYLPROPYLAMIDE and its SODIUMSALT AS PRODRUGS OF COX-2 INHIBITORS
HK99104900.3A HK1019741B (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors
DK97921092T DK0892791T3 (da) 1996-04-12 1997-04-11 N-[[4-(5-methyl-3-phenylisoxazol-4-yl]-phenyl]-sulfonylpropylamid og dets natriumsalt som prodrugs for COX-2-inhibitorer
RO98-01469A RO121338B1 (ro) 1996-04-12 1997-04-11 Derivaţi de benzensulfonamidă, procedeu de preparare a acestora, compoziţie farmaceutică şi utilizarea ca inhibitori de cox-2
EE9800351A EE03685B1 (et) 1996-04-12 1997-04-11 Asendatud benseensulfoonamiidi derivaadid kui COX-2 inhibiitorite eelravimid
JP53713997A JP3382624B2 (ja) 1996-04-12 1997-04-11 Ｃｏｘ―２阻害剤のプロドラッグとしての置換ベンゼンスルホンアミド誘導体
AU27227/97A AU734275C (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of COX-2 inhibitors
PL97329276A PL195955B1 (pl) 1996-04-12 1997-04-11 Związek, pochodna benzenosulfonamidu, sposób jegowytwarzania, kompozycja farmaceutyczna zawierająca go oraz jego zastosowanie
UA98115994A UA47475C2 (uk) 1996-04-12 1997-11-04 Похідні заміщеного бензолсульфонаміду, спосіб їх одержання та фармацевтична композиція
IS4863A IS2156B (is) 1996-04-12 1998-10-09 Settar bensensúlfonamíðafleiður sem forlyf fyrir COX-2 tálma, aðferð til þess að búa þær til, lyfjasamsetningar sem innihalda þær og notkun þeirra við framleiðslu lyfja
NO19984727A NO314184B1 (no) 1996-04-12 1998-10-09 Substituert benzensulfonamid derivater, fremgangsmåte for fremstilling av samme, farmasöytisk sammensetning innbefattende samme og anvendelseav samme forfremstilling av medikament
LVP-98-215A LV12239B (en) 1996-04-12 1998-10-12 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors
IS7292A IS7292A (is) 1996-04-12 2004-06-02 Staðgengnar bensensúlfonamíðafleiður sem forlyf fyrir COX-2 tálma
US10/939,852 US7420061B2 (en) 1996-04-12 2004-09-13 Process for preparing prodrugs of benzenesulfonamide-containing COX-2 inhibitors

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Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043648A1 (en) * 1997-04-03 1998-10-08 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of dementia
WO2000029022A1 (en) * 1998-11-12 2000-05-25 Algos Pharmaceutical Corporation Cox-2 inhibitors in combination with centrally acting analgesics
WO2000048583A3 (en) * 1999-02-19 2000-12-07 Pozen Inc Formulation of 5-ht agonists with nsaids, especially cox-2 inhibitors, for treating migraine
WO2001064669A1 (en) * 2000-03-03 2001-09-07 Pfizer Products Inc. Pyrazole ether derivatives as anti-inflammatory/analgesic agents
WO2001083475A1 (es) * 2000-04-25 2001-11-08 J. Uriach & Cia S.A. Nuevos compuestos heterociclicos con actividad antiinflamatoria
US6395724B1 (en) 1998-06-08 2002-05-28 Advanced Medicine, Inc. Multibinding inhibitors of cyclooxygenase-2
US6440963B1 (en) 2001-04-05 2002-08-27 Recordati S.A., Chemical And Pharmaceutical Company Use of selective COX-2 inhibitors for the treatment of urinary incontinence
WO2002083655A1 (en) * 2001-04-17 2002-10-24 Pharmacia Corporation Prodrugs of cox-2 inhibitors
WO2003024936A1 (en) * 2001-09-19 2003-03-27 Pharmacia Corporation Substituted pyrazolo compounds for the treatment of inflammation
US6586458B1 (en) 1996-08-16 2003-07-01 Pozen Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
WO2003013655A3 (en) * 2001-08-10 2003-08-14 Pharmacia Corp Carbonic anhydrase inhibitors
WO2003078408A1 (en) * 2002-03-15 2003-09-25 Pharmacia Corporation Crystalline parecoxib sodium
US6649629B2 (en) 1999-12-23 2003-11-18 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
WO2004058778A1 (en) * 2002-12-24 2004-07-15 J. Uriach Y Compañia S.A. New phosphoramide derivatives
WO2004060367A1 (en) * 2002-12-30 2004-07-22 Fujisawa Pharmaceutical Co., Ltd. Imidazole and triazole derivatives useful as selective cox-1 inhibitors
WO2004087682A1 (en) * 2003-04-04 2004-10-14 Hetero Drugs Limited Novel crystalline forms of parecoxib sodium
WO2004092146A3 (en) * 2003-04-14 2004-12-29 Inst For Pharm Discovery Inc N- (((((1,3-thiazol-2-yl) amino) carbonyl) phenyl) sulfonyl) phenylalanine derivatives and related compounds for the treatment of diabetes
US6887893B1 (en) 1997-12-24 2005-05-03 Sankyo Company, Limited Methods and compositions for treatment and prevention of tumors, tumor-related disorders and cachexia
WO2006011005A1 (en) * 2004-07-16 2006-02-02 Laboratorios Del Dr. Esteve, S.A. Derivatives of pyrazoline, procedure for obtaining them and use thereof as therapeutic agents
US7087630B2 (en) 2002-06-27 2006-08-08 Nitromed, Inc. Cyclooxygenase 2 selective inhibitors, compositions and methods of use
EP1061908A4 (en) * 1998-03-13 2007-01-24 Merck & Co Inc COMBINATION THERAPY AND COMPOSITION FOR ACUTE CORONARY MIXING SYNDROME AND ASSOCIATED CONDITIONS
WO2007012906A1 (en) * 2005-07-29 2007-02-01 Richter Gedeon Nyrt. New 1 , 2 -diaryl pyrazoles useful as analgetic and anti-inflammatory agents
US7211598B2 (en) 2002-06-28 2007-05-01 Nitromed, Inc. Oxime and/or hydrozone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7232821B2 (en) 2002-04-08 2007-06-19 Glaxo Group Limited (2-((2-alkoxy)-phenyl) -cyclopent-1enyl) aromatic carbo and heterocyclic acid and derivatives
EP0799823B1 (en) * 1996-04-05 2007-10-31 Daiichi Sankyo Company, Limited 1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses
EP1878725A2 (en) 2002-08-21 2008-01-16 Glaxo Group Limited Pyrimidine derivatives and their use as CB2 modulators
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
US7332183B2 (en) 2002-12-26 2008-02-19 Pozen Inc. Multilayer dosage forms containing NSAIDs and triptans
WO2008033931A1 (en) * 2006-09-13 2008-03-20 The Institutes For Pharmaceutical Discovery, Llc Para-xylylene carboxylic acids and isothiazolones useful as protein tyrosine phosphatases (ptps) in particular ptp-ib
US7358364B2 (en) 2003-04-30 2008-04-15 The Institute For Pharmaceutical Discovery Llc Substituted carboxylic acids
WO2008093919A1 (en) * 2007-01-30 2008-08-07 Dongbu Hitek Co., Ltd. Use of n-benzyl-n-(2-dimethylamino-ethyl)benzenesulfonamide derivatives for treating central nervous system disorders
WO2008107455A1 (en) 2007-03-07 2008-09-12 Glaxo Group Limited Indazoles used to treat estrogen receptor beta mediated disorders
US7446222B2 (en) 2002-11-01 2008-11-04 Glaxo Group Limited Phenyl compounds
US7470715B2 (en) 2005-12-22 2008-12-30 Pfizer Inc. Estrogen modulators
US7482462B2 (en) 2001-10-05 2009-01-27 Amarylla Horvath Acylsulfonamides as inhibitors of steroid sulfatase
US7521435B2 (en) 2005-02-18 2009-04-21 Pharma Diagnostics, N.V. Silicon containing compounds having selective COX-2 inhibitory activity and methods of making and using the same
EP2053042A1 (en) 2004-12-23 2009-04-29 Glaxo Group Limited Pyridine compounds for the treatment of prostaglandin mediated diseases
WO2010007074A1 (en) 2008-07-17 2010-01-21 Glaxo Group Limited Pyrazolo [1, 5-a] pyrimidine derivatives
WO2011012622A1 (en) 2009-07-30 2011-02-03 Glaxo Group Limited Benzoxazinone derivatives for the treatment of glytl mediated disorders
WO2011023753A1 (en) 2009-08-27 2011-03-03 Glaxo Group Limited Benzoxazine derivatives as glycine transport inhibitors
US7943658B2 (en) 2007-07-23 2011-05-17 Bristol-Myers Squibb Company Indole indane amide compounds useful as CB2 agonists and method
WO2011086377A1 (en) 2010-01-15 2011-07-21 Convergence Pharmaceuticals Limited PIPERAZINE DERIVATIVES FOR BLOCKING Cav2.2 CALCIUM CHANNELS
US8022095B2 (en) 1996-08-16 2011-09-20 Pozen, Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
WO2011141728A1 (en) 2010-05-10 2011-11-17 Convergence Pharmaceuticals Limited Spirocyclic derivatives with affinity for calcium channels
WO2011141729A1 (en) 2010-05-10 2011-11-17 Convergence Pharmaceuticals Limited Novel compounds
WO2012004604A1 (en) 2010-07-09 2012-01-12 Convergence Pharmaceuticals Limited Tetrazole compounds as calcium channel blockers
WO2012098400A1 (en) 2011-01-19 2012-07-26 Convergence Pharmaceuticals Limited Piperazine derivatives as cav2.2 calcium channel blockers
CN103119039A (zh) * 2010-08-20 2013-05-22 阿勒根公司 作用于多种前列腺素受体以产生广泛抗炎反应的化合物
WO2013093497A1 (en) 2011-12-22 2013-06-27 Convergence Pharmaceuticals Limited 2 - (pyridin- 2yl) - 1, 7 -diaza- spiro [4.4] nonane- 6 -one compounds as voltage - gated sodium channels modulators
US8530478B2 (en) 2008-07-17 2013-09-10 Convergence Pharmaceuticals Limited Piperazine derivatives used as CAV2.2 calcium channel modulators
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions
US8598152B2 (en) 2008-10-17 2013-12-03 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibs
EP2780009A4 (en) * 2011-11-17 2015-05-06 Univ Colorado Regents METHOD AND COMPOSITIONS FOR IMPROVED DRUG RELEASE INTO EYE AND FORMULATIONS WITH EXTENDED RELEASE
WO2016051195A1 (en) 2014-10-03 2016-04-07 Convergence Pharmaceuticals Limited Small fibre neuropathy treatment
WO2016051196A1 (en) 2014-10-03 2016-04-07 Convergence Pharmaceuticals Limited Paroxysmal extreme pain disorder treatment
WO2016051194A1 (en) 2014-10-03 2016-04-07 Convergence Pharmaceuticals Limited Erythromelalgia treatment
CN108164521A (zh) * 2018-03-02 2018-06-15 成都新恒创药业有限公司 一种帕瑞昔布钠降解杂质及其制备、检测方法和应用
WO2022195579A1 (en) 2021-03-15 2022-09-22 Saul Yedgar Hyaluronic acid-conjugated dipalmitoyl phosphatidyl ethanolamine in combination with non-steroidal anti-inflammatory drugs (nsaids) for treating or alleviating inflammatory diseases

Families Citing this family (226)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038418A1 (en) 1995-06-02 1996-12-05 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
PT1288206E (pt) * 1996-04-12 2008-11-14 Searle Llc Derivados de benzenossulfonamida substituídos como pró-fármacos de inibidores de cox-2
US20040072889A1 (en) * 1997-04-21 2004-04-15 Pharmacia Corporation Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
RS49982B (sr) 1997-09-17 2008-09-29 Euro-Celtique S.A., Sinergistička analgetička kombinacija analgetičkog opijata i inhibitora ciklooksigenaze-2
US6136804A (en) * 1998-03-13 2000-10-24 Merck & Co., Inc. Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
AR024222A1 (es) * 1998-10-16 2002-09-25 Palau Pharma Sa Imidazoles con actividad antiinflamatoria un procedimiento para su preparacion y composiciones farmaceuticas que lo contienen
EP1126841B1 (en) * 1998-11-02 2004-12-15 Merck & Co., Inc. Combinations of a 5ht1b/1d agonist and a selective cox-2 inhibitor for the treatment of migraine
US20030119895A1 (en) * 1998-12-23 2003-06-26 Pharmacia Corporation Methods using a combination of a 3-heteroaryl-2-indolinone and a cyclooxygenase-2 inhibitor for the treatment of neoplasia
US6649645B1 (en) * 1998-12-23 2003-11-18 Pharmacia Corporation Combination therapy of radiation and a COX-2 inhibitor for treatment of neoplasia
US20040122011A1 (en) * 1998-12-23 2004-06-24 Pharmacia Corporation Method of using a COX-2 inhibitor and a TACE inhibitors as a combination therapy
US20030013739A1 (en) * 1998-12-23 2003-01-16 Pharmacia Corporation Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia
US20010024664A1 (en) * 1999-03-19 2001-09-27 Obukowicz Mark G. Selective COX-2 inhibition from edible plant extracts
WO2001028548A1 (en) * 1999-10-19 2001-04-26 Texas Heart Institute Treatment of heart disease with cox-2 inhibitors
ES2236007T3 (es) * 1999-12-08 2005-07-16 Pharmacia Corporation Composiciones de inhibidor de ciclooxigenasa-2 ue tiene un efecto terapeutico rapido.
WO2001045706A1 (en) * 1999-12-22 2001-06-28 Pharmacia Corporation Dual-release compositions of a cyclooxygenase-2- inhibitor
AU2001238468B2 (en) 2000-02-16 2006-07-06 The Brigham And Women's Hospital, Inc. Aspirin-triggered lipid mediators
US20070072861A1 (en) * 2000-03-27 2007-03-29 Barbara Roniker Method of using cyclooxygenase-2 inhibitors in the prevention of cardiovascular disorders
WO2001081333A2 (en) * 2000-04-25 2001-11-01 Pharmacia Corporation Regioselective synthesis of 3,4-di(carbocyclyl or heterocyclyl)thiophenes
EP1299123A2 (en) * 2000-07-13 2003-04-09 Pharmacia Corporation Use of cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
CA2415577C (en) 2000-07-20 2010-10-19 Lauras As Use of cox-2 inhibitors for preventing immunodeficiency
US20030219461A1 (en) * 2000-09-12 2003-11-27 Britten Nancy J. Parenteral combination therapy for infective conditions
JP2004508401A (ja) * 2000-09-18 2004-03-18 メルク　エンド　カムパニー　インコーポレーテッド シクロオキシゲナーゼ−２阻害剤およびインテグリンアルファ−ｖアンタゴニストの組合せを用いる炎症の治療
CA2425259A1 (en) * 2000-10-11 2002-04-18 Tularik, Inc. Modulation of ccr4 function
WO2002047707A2 (en) * 2000-12-15 2002-06-20 Pharmacia Corporation Selective cox-2 inhibition from non-edible plant extracts
EP1401460A2 (en) * 2000-12-15 2004-03-31 Pharmacia Corporation Selective cox-2 inhibition from plant extracts
JP4092203B2 (ja) 2000-12-21 2008-05-28 ニトロメッド，インク． 新規のシクロオキシゲナーゼ２選択的阻害剤としての置換アリール化合物、組成物、および使用方法
US7115565B2 (en) * 2001-01-18 2006-10-03 Pharmacia & Upjohn Company Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability
JP2004522754A (ja) * 2001-02-02 2004-07-29 ファルマシア・コーポレーション 月経困難症の治療および予防のための組み合わせ治療としてシクロオキシゲナーゼ‐２阻害剤および性ステロイドを使用する方法
AU2002306868A1 (en) * 2001-03-28 2002-10-15 Pharmacia Corporation Therapeutic combinations for cardiovascular and inflammatory indications
US7695736B2 (en) * 2001-04-03 2010-04-13 Pfizer Inc. Reconstitutable parenteral composition
US6673818B2 (en) 2001-04-20 2004-01-06 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
US7144903B2 (en) * 2001-05-23 2006-12-05 Amgen Inc. CCR4 antagonists
US20030153801A1 (en) * 2001-05-29 2003-08-14 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and radiation for inhibition or prevention of cardiovascular disease
JP2004532871A (ja) * 2001-05-31 2004-10-28 ファルマシア・コーポレーション 皮膚浸透性シクロオキシゲナーゼ−２選択的阻害組成物
DE10129320A1 (de) * 2001-06-19 2003-04-10 Norbert Mueller Verwendung von COX-2 Inhibitoren zur Behandlung von Schizophrenie, wahnhaften Störungen, affektiven Störungen oder Ticstörungen
US20060167074A1 (en) * 2001-06-19 2006-07-27 Norbert Muller Methods and compositions for the treatment of psychiatric disorders
UA80682C2 (en) * 2001-08-06 2007-10-25 Pharmacia Corp Orally deliverable stabilized oral suspension formulation and process for the incresaing physical stability of thixotropic pharmaceutical composition
US20040067992A1 (en) * 2001-08-10 2004-04-08 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a carbonic anhydrase inhibitor for the treatment of neoplasia
US20030114416A1 (en) * 2001-08-14 2003-06-19 Pharmacia Corporation Method and compositions for the treatment and prevention of pain and inflammation with a cyclooxygenase-2 selective inhibitor and chondroitin sulfate
US20050101563A1 (en) * 2001-08-14 2005-05-12 Pharmacia Corporation Method and compositions for the treatment and prevention of pain and inflammation
MXPA04002242A (es) * 2001-09-10 2005-03-07 Sugen Inc Derivados de 3-(4,5,6,7,-tetrahidroindol-2-ilmetiliden)-2-indolinona como inhibidores de cinasa.
US20030114483A1 (en) * 2001-09-18 2003-06-19 Pharmacia Corporation Compositions of chromene cyclooxygenase-2 selective inhibitors and acetaminophen for treatment and prevention of inflammation, inflammation-mediated disorders and pain
AU2002330042A1 (en) 2001-09-18 2003-04-01 Onconova Therapeutics, Inc. Process for the preparation of 1,5-diarylpyrazoles
NZ532346A (en) * 2001-09-18 2005-10-28 Onconova Therapeutics Inc Processes for the preparation of 1,5-diaryl-3-substituted-pyrazoles
US20030236308A1 (en) * 2001-09-18 2003-12-25 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and acetaminophen for treatment and prevention of inflammation, inflammation-mediated disorders and pain
US20030105334A1 (en) * 2001-10-02 2003-06-05 Letendre Leo J. Method for preparing benzenesulfonyl compounds
US6809204B2 (en) * 2001-10-12 2004-10-26 Onconova Therapeutics, Inc. Processes for the preparation of substituted isoxazoles and 2-isoxazolines
US20030162824A1 (en) * 2001-11-12 2003-08-28 Krul Elaine S. Methods of treating or preventing a cardiovascular condition using a cyclooxygenase-1 inhibitor
BR0214081A (pt) * 2001-11-13 2004-09-28 Pharmacia Corp Forma de dosagem oral de uma pró-droga de sulfonamida
DE60231439D1 (de) 2001-12-06 2009-04-16 Merck & Co Inc Mitotische kinesinhemmer
AU2002353147A1 (en) * 2001-12-13 2003-06-30 Abbott Laboratories 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
US20040126438A1 (en) * 2001-12-13 2004-07-01 Obukowicz Mark G. Selective cox-2 inhibition from plant extracts
US20040062823A1 (en) * 2001-12-13 2004-04-01 Obukowicz Mark G. Selective cox-2 inhibition from non-edible plant extracts
BR0306820A (pt) * 2002-01-10 2004-12-07 Pharmacia & Up John Company Uso de inibidores cox-2 em combinação com agentes antivirais para o tratamento de infecções de papilomavìrus
US20030212138A1 (en) * 2002-01-14 2003-11-13 Pharmacia Corporation Combinations of peroxisome proliferator-activated receptor-alpha agonists and cyclooxygenase-2 selective inhibitors and therapeutic uses therefor
US20030220374A1 (en) * 2002-01-14 2003-11-27 Pharmacia Corporation Compositions and methods of treatment involving peroxisome proliferator-activated receptor-gamma agonists and cyclooxygenase-2 selective inhibitors
TW200403072A (en) * 2002-01-23 2004-03-01 Upjohn Co Combination therapy for the treatment of bacterial infections
US20030224006A1 (en) 2002-03-01 2003-12-04 Zaworotko Michael J. Multiple-component solid phases containing at least one active pharmaceutical ingredient
US7927613B2 (en) * 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
US20100311701A1 (en) * 2002-02-15 2010-12-09 Transform Pharmaceuticals, Inc Pharmaceutical Co-Crystal Compositions
US7790905B2 (en) * 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
EP1915992A1 (en) 2002-02-19 2008-04-30 Pharmacia Corporation Use of cyclooxygenase inhibitors and antimuscarinic agents for the treatment of incontinence
US7902257B2 (en) 2002-04-01 2011-03-08 University Of Southern California Trihydroxy polyunsaturated eicosanoid
US8481772B2 (en) 2002-04-01 2013-07-09 University Of Southern California Trihydroxy polyunsaturated eicosanoid derivatives
CA2482510A1 (en) * 2002-04-18 2003-10-30 Pharmacia Corporation Monotherapy for the treatment of parkinson`s disease with cyclooxygenase-2 (cox 2) inhibitor(s)
US20040034083A1 (en) * 2002-04-18 2004-02-19 Stephenson Diane T. Combination therapy for the treatment of Parkinson's disease with cyclooxygenase-2 (COX2) inhibitor(s)
US7273616B2 (en) * 2002-05-10 2007-09-25 The Trustees Of Columbia University In The City Of New York Genetically engineered cell lines and systems for propagating Varicella zoster virus and methods of use thereof
CA2489984A1 (en) * 2002-06-21 2003-12-31 Transform Pharmaceuticals, Inc. Pharmaceutical compositions with improved dissolution
WO2004002533A1 (en) * 2002-06-26 2004-01-08 Pharmacia Corporation Stable liquid parenteral parecoxib formulation
AU2003248759A1 (en) * 2002-07-02 2004-01-23 Pharmacia Corporation Use of cyclooxygenase-2 selective inhibitors and thrombolytic agents for the treatment or prevention of a vaso-occlusive event
US7759395B2 (en) 2002-08-12 2010-07-20 The Brigham And Women's Hospital, Inc. Use of docosatrienes, resolvins and their stable analogs in the treatment of airway diseases and asthma
ATE449057T1 (de) * 2002-08-12 2009-12-15 Brigham & Womens Hospital Resolvine: biotemplate zur durchführung therapeutischer anwendungen
US20060052432A1 (en) * 2002-09-20 2006-03-09 Julius Remenar Pharmaceutical compositions with improved dissolution
KR100484525B1 (ko) * 2002-10-15 2005-04-20 씨제이 주식회사 이소티아졸 유도체, 그 제조방법 및 약제학적 조성물
US20040082543A1 (en) * 2002-10-29 2004-04-29 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
US20040092566A1 (en) * 2002-11-12 2004-05-13 Graneto Matthew J. Celecoxib prodrug
US20040147581A1 (en) * 2002-11-18 2004-07-29 Pharmacia Corporation Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy
US20040127531A1 (en) * 2002-11-21 2004-07-01 Lu Guang Wei Adhesive coated sheet for dermal delivery of a selective cyclooxygenase-2 inhibitor
US20040126415A1 (en) * 2002-11-21 2004-07-01 Lu Guang Wei Dermal delivery of a water-soluble selective cyclooxygenase-2 inhibitor
US20050020658A1 (en) * 2002-11-21 2005-01-27 Katsuyuki Inoo Selective cyclooxygenase-2 inhibitor patch
KR20050085563A (ko) 2002-12-13 2005-08-29 워너-램버트 캄파니 엘엘씨 하부요로증상을 치료하기 위한 알파-2-델타 리간드
US20040235925A1 (en) * 2002-12-17 2004-11-25 Pharmacia Corporation Method for the treatment, prevention, or inhibition of a CNS disorder and/or pain and inflammation using a combination of duloxetine, venlafaxine or atomoxetine and a cyclooxygenase-2 selective inhibitor and compositions thereof
US20040204411A1 (en) * 2002-12-17 2004-10-14 Pharmacia Corporation Method for the treatment, prevention, or inhibition of a CNS disorder and/or pain and inflammation using a combination of reboxetine and a cyclooxygenase-2 selective inhibitor and compositions thereof
US20040157848A1 (en) * 2002-12-19 2004-08-12 Pharmacia Corporation Methods and compositions for the treatment of herpes virus infections using cyclooxygenase-2 selective inhibitors or cyclooxygenase-2 inhibitors in combination with antiviral agents
US20080153894A1 (en) * 2002-12-19 2008-06-26 Pharmacia Corporation Cyclooxygenase-2 inhibitor and antibacterial agent combination for intramammary treatment of mastitis
AU2003300264A1 (en) * 2002-12-20 2004-07-22 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and selective serotonin reuptake inhibitors for the treatment or prevention of a vaso-occlusive event
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
US20050026902A1 (en) * 2003-01-31 2005-02-03 Timothy Maziasz Methods and compositions for the treatment or prevention of human immunodeficiency virus and related conditions using cyclooxygenase-2 selective inhibitors and antiviral agents
US20040176378A1 (en) * 2003-02-12 2004-09-09 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and an amphetamine for the treatment of reduced blood flow to the central nervous system
WO2004078143A2 (en) * 2003-03-05 2004-09-16 The Brigham And Women's Hospital Inc. Methods for identification and uses of anti-inflammatory receptors for eicosapentaenoic acid analogs
US20050009931A1 (en) * 2003-03-20 2005-01-13 Britten Nancy Jean Dispersible pharmaceutical composition for treatment of mastitis and otic disorders
US20050004098A1 (en) * 2003-03-20 2005-01-06 Britten Nancy Jean Dispersible formulation of an anti-inflammatory agent
CN1761487A (zh) * 2003-03-20 2006-04-19 法玛西雅公司 抗炎剂的可分散制剂
US20040214753A1 (en) * 2003-03-20 2004-10-28 Britten Nancy Jean Dispersible pharmaceutical composition for treatment of mastitis and otic disorders
US20040220155A1 (en) * 2003-03-28 2004-11-04 Pharmacia Corporation Method of providing a steroid-sparing benefit with a cyclooxygenase-2 inhibitor and compositions therewith
US20040214861A1 (en) * 2003-03-28 2004-10-28 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitors and 5-HT1B1D antagonists for the treatment and prevention of migraine
US20040224940A1 (en) * 2003-04-22 2004-11-11 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a sodium ion channel blocker for the treatment of central nervous system damage
US20050159403A1 (en) * 2003-04-22 2005-07-21 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a calcium modulating agent for the treatment of central nervous system damage
WO2004093813A2 (en) * 2003-04-22 2004-11-04 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a calcium modulating agent for the treatment of pain, inflammation or inflammation mediated disorders
US20050009733A1 (en) * 2003-04-22 2005-01-13 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of central nervous system damage
US20040229803A1 (en) * 2003-04-22 2004-11-18 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of pain, inflammation or inflammation mediated disorders
US20040220187A1 (en) * 2003-04-22 2004-11-04 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a sodium ion channel blocker for the treatment of pain, inflammation or inflammation mediated disorders
US20040220167A1 (en) * 2003-05-02 2004-11-04 Nasrollah Samiy Methods of treating neuralgic pain
US20050107387A1 (en) * 2003-05-13 2005-05-19 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a peroxisome proliferator activated receptor agonist for the treatment of ischemic mediated central nervous system disorders
CA2525280A1 (en) * 2003-05-14 2004-12-02 Pharmacia Corporation Compositions for the treatment of reduced blood flow
WO2004103286A2 (en) * 2003-05-14 2004-12-02 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a cholimergic agent
CA2525571A1 (en) * 2003-05-14 2004-12-02 Pharmacia Corporation Compositions of a benzenesulfonamide or methylsulfonylbenzene cyclooxygenase-2 selective inhibitor and a cholinergic agent for the treatment of reduced blood flow or trauma to thecentral nervous system
US20050159419A1 (en) * 2003-05-14 2005-07-21 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a central nervous system stimulant for the treatment of central nervous system damage
US20050113376A1 (en) * 2003-05-27 2005-05-26 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor, a xanthine compound and an alcohol for the treatment of ischemic mediated central nervous system disorders or injury
WO2004105699A2 (en) * 2003-05-28 2004-12-09 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a cannabinoid agent for the treatment of central nervous system damage
CN1812983A (zh) 2003-05-30 2006-08-02 兰贝克赛实验室有限公司 取代的吡咯衍生物及其作为hmg－co抑制剂的用途
US20050054646A1 (en) * 2003-06-09 2005-03-10 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and an antioxidant agent for the treatment of central nervous system disorders
BRPI0411731A (pt) * 2003-06-24 2006-08-08 Pharmacia Corp tratamento de enxaqueca acompanhada por náusea
US20050101597A1 (en) * 2003-07-10 2005-05-12 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitior and a non-NMDA glutamate modulator for the treatment of central nervous system damage
WO2005007156A1 (en) * 2003-07-10 2005-01-27 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and an angiotensin ii receptor antagonist for the treatment of central nervous system damage
US20050070543A1 (en) * 2003-07-11 2005-03-31 Pharmacia Corporation Compositions of a chromene or phenyl acetic acid cyclooxygenase-2 selective inhibitor and an ACE inhibitor for the treatment of central nervous system damage
US20050080084A1 (en) * 2003-07-11 2005-04-14 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a serotonin-modulating agent for the treatment of central nervous system damage
WO2005009342A2 (en) * 2003-07-16 2005-02-03 Pharmacia Corporation Method for the treatment or prevention of dermatological disorders with a cyclooxygenase-2 inhibitor alone and in combination with a dermatological treatment agent and compositions therewith
US20050075341A1 (en) * 2003-07-17 2005-04-07 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and an IKK inhibitor for the treatment of ischemic mediated central nervous system disorders or injury
WO2005012268A1 (ja) * 2003-07-30 2005-02-10 Shionogi & Co., Ltd. イソオキサゾール環を有するスルホンアミド誘導体
EP1670459A4 (en) * 2003-08-20 2009-03-25 Nitromed Inc NITROSED AND NITROSYLATED CARDIOVASCULAR COMPOUNDS, COMPOSITIONS AND APPLICATION METHODS
US20050119262A1 (en) * 2003-08-21 2005-06-02 Pharmacia Corporation Method for preventing or treating an optic neuropathy with a cox-2 inhibitor and an intraocular pressure reducing agent
US20050085478A1 (en) * 2003-08-22 2005-04-21 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a low-molecular-weight heparin for the treatment of central nervous system damage
US20050107350A1 (en) * 2003-08-22 2005-05-19 Pharmacia Corporation Method for the treatment or prevention of bone disorders with a cyclooxygenase-2 inhibitor alone and in combination with a bone disorder treatment agent and compositions therewith
US20050130971A1 (en) * 2003-08-22 2005-06-16 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and phosphodiesterase inhibitor for the treatment of ischemic mediated central nervous system disorders or injury
EP1660079A2 (en) * 2003-08-22 2006-05-31 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a serotonin modulating agent for the treatment of neoplasia
WO2005020910A2 (en) * 2003-08-27 2005-03-10 Pharmacia Corporation Cyclooxygenase-2 selective inhibitor and corticotropin releasing factor antagonist compositions for treating ischemic mediated cns disorders or injuries
AU2004270161A1 (en) * 2003-08-28 2005-03-17 Nicox S.A. Nitrosated and nitrosylated cardiovascular compounds, compositions and methods of use
US20050187278A1 (en) * 2003-08-28 2005-08-25 Pharmacia Corporation Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors
US20050113409A1 (en) * 2003-09-03 2005-05-26 Pharmacia Corporation Method for the prevention or treatment of pain, inflammation and inflammation-related disorders with a Cox-2 selective inhibitor in combination with a nitric oxide-donating agent and compositions therewith
US20050113434A1 (en) * 2003-10-03 2005-05-26 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor administered under hypothermic conditions for the treatment of ischemic mediated central nervous system disorders or injury
EP1684784A2 (en) * 2003-11-12 2006-08-02 Pharmacia & Upjohn Company LLC Compositions of a cyclooxygenase-2 selective inhibitor and a neurotrophic factor-modulating agent for the treatment of central nervous system mediated disorders
EP1708700A1 (en) * 2003-12-24 2006-10-11 Pharmacia Corporation Metal salts of parecoxib as prodrugs of the cox-2 inhibitor valdecoxib for the treatment of inflammation, pain and/or fever
BRPI0506994A (pt) 2004-01-22 2007-07-03 Pfizer derivados de triazol que inibem a atividade antagonista da vasopressina
US20050238589A1 (en) * 2004-04-14 2005-10-27 Van Dyke Thomas E Methods and compositions for preventing or treating periodontal diseases
JP2007534740A (ja) * 2004-04-28 2007-11-29 ファイザー・インク バソプレッシンＶ１ａ受容体の阻害剤としての３−ヘテロシクリル−４−フェニル−トリアゾール誘導体
WO2006007491A1 (en) 2004-07-01 2006-01-19 Merck & Co., Inc. Mitotic kinesin inhibitors
BRPI0513695A (pt) * 2004-07-22 2008-05-13 Pharmacia Corp composições para o tratamento de inflamação e dor que empregam uma combinação de um inibidor seletivo de cox-2 e um antagonista de receptor ltb4
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
EP1814535A4 (en) * 2004-11-08 2008-06-04 Nitromed Inc NITROSED AND NITROSYLATED COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING EYE DISEASES
CA2595579A1 (en) * 2005-01-21 2006-07-27 Nitromed, Inc. Cardiovascular compounds comprising heterocyclic nitric oxide donor group compositions and methods of use
JP2008530226A (ja) * 2005-02-16 2008-08-07 ニトロメッド インコーポレーティッド 抗微生物化合物の有機酸化窒素供与体塩、組成物、および使用法
AU2006218766A1 (en) * 2005-02-28 2006-09-08 Nicox S.A. Cardiovascular compounds comprising nitric oxide enhancing groups, compositions and methods of use
AP2552A (en) 2005-04-26 2013-01-08 Pfizer P-cadherin antibodies
CA2607913C (en) * 2005-05-05 2014-03-18 Cook Biotech Incorporated Implantable materials and methods for inhibiting tissue adhesion formation
WO2006123182A2 (en) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Cyclohexyl sulphones for treatment of cancer
JP2008540633A (ja) * 2005-05-18 2008-11-20 ファイザー・リミテッド バソプレッシン拮抗薬としての１，２，４−トリアゾール誘導体
EP1883614A4 (en) * 2005-05-23 2010-04-14 Nicox Sa ORGANIC NITRIC OXIDES IMPROVING SALTS FROM NON-SUBSTITUTE INFLAMMATORY COMPOUNDS AND COMPOSITIONS AND USES THEREOF
EP1915157A4 (en) * 2005-08-02 2010-09-01 Nicox Sa NICKEL OXYGENIZING ANTIMICROBIAL COMPOUNDS, COMPOSITIONS AND USE PROCESSES
TWI387592B (zh) * 2005-08-30 2013-03-01 Novartis Ag 經取代之苯并咪唑及其作為與腫瘤形成相關激酶之抑制劑之方法
PL1933871T3 (pl) * 2005-09-07 2013-09-30 Amgen Fremont Inc Ludzkie przeciwciała monoklonalne przeciwko kinazie podobnej do recepora aktywiny-1
US8273792B2 (en) 2005-10-03 2012-09-25 The Brigham And Women's Hospital, Inc. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and it's natural stereoisomers
US20090054381A1 (en) * 2005-10-04 2009-02-26 Nitromed, Inc. Methods for treating respiratory disorders
KR101329112B1 (ko) 2005-11-08 2013-11-14 랜박시 래보러터리스 리미티드 (3ｒ,5ｒ)-7-〔2-(4-플루오로페닐)-5-이소프로필-3-페닐-4-〔(4-히드록시 메틸 페닐 아미노)카르보닐〕-피롤-1-일〕-3,5-디히드록시 헵탄산 헤미 칼슘염의 제조 방법
EP1954685A4 (en) * 2005-11-16 2009-11-11 Nitromed Inc FUROXANE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
US8636986B2 (en) 2005-11-18 2014-01-28 The Forsyth Institute Treatment and prevention of bone loss using resolvins
WO2007075541A2 (en) * 2005-12-20 2007-07-05 Nitromed, Inc. Nitric oxide enhancing glutamic acid compounds, compositions and methods of use
EP1971340A2 (en) * 2005-12-22 2008-09-24 Nitromed, Inc. Nitric oxide enhancing pyruvate compounds, compositions and methods of use
US20090062302A1 (en) 2006-01-24 2009-03-05 Buser-Doepner Carolyn A Jak2 Tyrosine Kinase Inhibition
GB0603041D0 (en) 2006-02-15 2006-03-29 Angeletti P Ist Richerche Bio Therapeutic compounds
EP2007705A4 (en) 2006-03-29 2011-09-07 Nicox Sa NITROGEN MONOXIDE REINFORCING PROSTAGLANDIN COMPOUNDS, COMPOSITION AND APPLICATION PROCESS
JP5328640B2 (ja) 2006-04-19 2013-10-30 ノバルティス アーゲー ６−ｏ−置換ベンゾオキサゾールおよびベンゾチアゾール化合物ならびにｃｓｆ−１ｒシグナル伝達を阻害する方法
EP2027087A2 (en) 2006-05-18 2009-02-25 MannKind Corporation Intracellular kinase inhibitors
AU2007300627B2 (en) 2006-09-22 2012-02-16 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
US20110218176A1 (en) 2006-11-01 2011-09-08 Barbara Brooke Jennings-Spring Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
PL2125021T3 (pl) 2006-12-22 2011-10-31 Recordati Ireland Ltd Leczenie skojarzone zaburzeń w obrębie dolnych dróg moczowych z zastosowaniem ligandów α2δ i przeciwzapalnych leków niesterydowych (NSAIDs)
PL2336120T3 (pl) 2007-01-10 2014-12-31 Msd Italia Srl Kombinacje zawierające indazole podstawione grupą amidową jako inhibitory polimerazy poli(ADP-rybozy) (PARP)
ES2431163T3 (es) 2007-03-01 2013-11-25 Novartis Ag Inhibidores de PIM quinasa y métodos para su uso
BRPI0812159A2 (pt) 2007-05-21 2017-05-02 Novartis Ag inibidores de csf-1r, composições e métodos de uso
EP3103791B1 (en) 2007-06-27 2018-01-31 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
CA2692977A1 (en) 2007-07-12 2009-01-15 Tragara Pharmaceuticals, Inc. Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders
KR101257550B1 (ko) 2007-09-10 2013-04-24 칼시메디카, 인크 세포내 칼슘을 조절하는 화합물
CN102014631A (zh) 2008-03-03 2011-04-13 泰格尔医药科技公司 酪氨酸激酶抑制剂
BRPI0917719A2 (pt) 2008-08-27 2019-11-19 Calcimedica Inc compostos que modulam cálcio intracelular
JP5212177B2 (ja) * 2009-02-27 2013-06-19 東レ株式会社 γ−ケトアセタール化合物及びピロール誘導体の製造方法
GB0903493D0 (en) 2009-02-27 2009-04-08 Vantia Ltd New compounds
KR101069175B1 (ko) 2009-04-19 2011-09-30 중앙대학교 산학협력단 신규 아미노설포닐아릴이소옥사졸계 화합물 및 이를 포함하는 다약제내성 억제용 약제학적 조성물
NZ599343A (en) 2009-10-14 2014-05-30 Merck Sharp & Dohme Substituted piperidines that increase p53 activity and the uses thereof
CN101805290A (zh) * 2010-04-01 2010-08-18 中国人民解放军第四军医大学 氨基磺酰吡唑类化合物及其用途
CA2797533A1 (en) 2010-04-27 2011-11-10 Calcimedica, Inc. Compounds that modulate intracellular calcium
EP2563776B1 (en) 2010-04-27 2016-06-08 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2011145022A1 (en) 2010-05-21 2011-11-24 Pfizer Inc. 2-phenyl benzoylamides
US8999957B2 (en) 2010-06-24 2015-04-07 Merck Sharp & Dohme Corp. Heterocyclic compounds as ERK inhibitors
AU2011285909B2 (en) 2010-08-02 2016-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (CTNNB1) gene expression using short interfering nucleic acid (siNA)
WO2012024170A2 (en) 2010-08-17 2012-02-23 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS B VIRUS (HBV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
EP2608669B1 (en) 2010-08-23 2016-06-22 Merck Sharp & Dohme Corp. NOVEL PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS
JP5916149B2 (ja) 2010-08-27 2016-05-11 カルシメディカ，インク． 細胞内カルシウムを調節する化合物
US8946216B2 (en) 2010-09-01 2015-02-03 Merck Sharp & Dohme Corp. Indazole derivatives useful as ERK inhibitors
US9242981B2 (en) 2010-09-16 2016-01-26 Merck Sharp & Dohme Corp. Fused pyrazole derivatives as novel ERK inhibitors
WO2012058210A1 (en) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA)
EP2654748B1 (en) 2010-12-21 2016-07-27 Merck Sharp & Dohme Corp. Indazole derivatives useful as erk inhibitors
JP2014513923A (ja) 2011-03-04 2014-06-19 ファイザー・インク Ｅｄｎ３様ペプチドおよびその使用
US20140046059A1 (en) 2011-04-21 2014-02-13 Piramal Enterprises Limited Process for the preparation of morpholino sulfonyl indole derivatives
EP2770987B1 (en) 2011-10-27 2018-04-04 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
WO2013066729A1 (en) 2011-10-31 2013-05-10 Merck Sharp & Dohme Corp. Aminopyrimidinones as interleukin receptor-associated kinase inhibitors
EP3358013B1 (en) 2012-05-02 2020-06-24 Sirna Therapeutics, Inc. Short interfering nucleic acid (sina) compositions
WO2014052563A2 (en) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
US9512116B2 (en) 2012-10-12 2016-12-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
HUE035662T2 (en) 2012-11-28 2018-05-28 Merck Sharp & Dohme Compositions and methods for treating cancer
MX373639B (es) 2012-12-20 2020-05-04 Merck Sharp & Dohme Imidazopiridinas sustituidas como inhibidores de doble minuto 2 humana.
US9540377B2 (en) 2013-01-30 2017-01-10 Merck Sharp & Dohme Corp. 2,6,7,8 substituted purines as HDM2 inhibitors
NZ712479A (en) * 2013-03-15 2019-01-25 Univ Southern California Methods, compounds, and compositions for the treatment of angiotensin-related diseases
EP3019171B1 (en) 2013-07-11 2018-09-05 Merck Sharp & Dohme Corp. Substituted amidopyrazole inhibitors of interleukin receptor-associated kinases (irak-4)
US20160194368A1 (en) 2013-09-03 2016-07-07 Moderna Therapeutics, Inc. Circular polynucleotides
CN104418818B (zh) * 2013-09-04 2017-01-11 天津汉瑞药业有限公司 帕瑞昔布钠无水化合物
WO2015054283A1 (en) 2013-10-08 2015-04-16 Calcimedica, Inc. Compounds that modulate intracellular calcium
CN105085425B (zh) * 2014-05-23 2018-01-30 昆药集团股份有限公司 一种制备帕瑞昔布的方法
JO3589B1 (ar) 2014-08-06 2020-07-05 Novartis Ag مثبطات كيناز البروتين c وطرق استخداماتها
CN104557754A (zh) * 2015-01-04 2015-04-29 成都克莱蒙医药科技有限公司 一种帕瑞昔布钠杂质的合成方法
EP3268367B8 (en) 2015-03-12 2022-11-16 Merck Sharp & Dohme LLC Carboxamide inhibitors of irak4 activity
US10329294B2 (en) 2015-03-12 2019-06-25 Merck Sharp & Dohme Corp. Pyrazolopyrimidine inhibitors of IRAK4 activity
EP3268003B1 (en) 2015-03-12 2020-07-29 Merck Sharp & Dohme Corp. Thienopyrazine inhibitors of irak4 activity
SI3328827T1 (sl) * 2015-07-31 2023-11-30 The Johns Hopkins University Predzdravila glutamin analogov
US9598361B1 (en) * 2016-04-12 2017-03-21 King Saud University Amino substituted acetamide derivative
WO2018049027A1 (en) 2016-09-07 2018-03-15 Trustees Of Tufts College Combination therapies using immuno-dash inhibitors and pge2 antagonists
EP3525785B1 (en) 2016-10-12 2025-08-27 Merck Sharp & Dohme LLC Kdm5 inhibitors
US11098059B2 (en) 2017-11-08 2021-08-24 Merck Sharp & Dohme Corp. PRMT5 inhibitors
EP3706742B1 (en) 2017-11-08 2023-03-15 Merck Sharp & Dohme LLC Prmt5 inhibitors
CN108299331A (zh) * 2018-03-02 2018-07-20 成都新恒创药业有限公司 一种帕瑞昔布钠光降解杂质及其制备、检测方法和应用
BR112021002267A8 (pt) 2018-08-07 2023-02-07 Merck Sharp & Dohme Inibidores de prmt5
WO2020033282A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
US11981701B2 (en) 2018-08-07 2024-05-14 Merck Sharp & Dohme Llc PRMT5 inhibitors
CN110305071A (zh) * 2019-07-23 2019-10-08 成都通德药业有限公司 一种帕瑞昔布钠中间体帕瑞昔布的合成方法
JP7589247B2 (ja) 2019-12-17 2024-11-25 メルク・シャープ・アンド・ドーム・エルエルシー Ｐｒｍｔ５阻害剤
WO2021126728A1 (en) 2019-12-17 2021-06-24 Merck Sharp & Dohme Corp. Prmt5 inhibitors
CN115784991B (zh) * 2022-11-22 2025-01-24 合肥医工医药股份有限公司 N-(苯磺酰基)酰胺衍生物及其制备方法和用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5344991A (en) * 1993-10-29 1994-09-06 G.D. Searle & Co. 1,2 diarylcyclopentenyl compounds for the treatment of inflammation
WO1994027980A1 (en) * 1993-05-21 1994-12-08 G.D. Searle & Co. Substituted oxazolyl compounds for the treatment of inflammation
WO1995000501A2 (en) * 1993-06-24 1995-01-05 Merck Frosst Canada Inc. Phenyl heterocycles as cyclooxygenase-2 inhibitors
WO1995015316A1 (en) * 1993-11-30 1995-06-08 G. D. Searle & Co. Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
WO1995021817A1 (en) * 1994-02-10 1995-08-17 G.D. Searle & Co. Substituted spiro compounds for the treatment of inflammation
WO1996003388A1 (en) * 1994-07-28 1996-02-08 G.D. Searle & Co. 1,2-substituted imidazolyl compounds for the treatment of inflammation

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US538738A (en) 1895-05-07 Measuring-faucet
GB911204A (en) 1960-07-28 1962-11-21 Unilever Ltd Bleaching compositions
US4146721A (en) 1969-09-12 1979-03-27 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyrazol-4-acetic acid compounds
US3984431A (en) 1972-03-15 1976-10-05 Claude Gueremy Derivatives of pyrazole-5-acetic acid
DE3321082C2 (de) 1982-06-10 1996-08-22 Kao Corp Bleich-Reinigungsmittel
JPS59145300A (ja) 1983-02-07 1984-08-20 日本パ−オキサイド株式会社 漂白洗剤
JPS6015500A (ja) 1983-07-08 1985-01-26 ライオン株式会社 高嵩密度洗剤組成物
JPS60118606A (ja) 1983-11-28 1985-06-26 Mitsubishi Gas Chem Co Inc 安定化された過炭酸ナトリウム粒状物
US5051518A (en) 1987-05-29 1991-09-24 Ortho Pharmaceutical Corporation Pharmacologically active 2- and 3-substituted (1',5'-diaryl-3-pyrazolyl)-N-hydroxypropanamides
JP2590124B2 (ja) * 1987-08-12 1997-03-12 国際試薬株式会社 水溶性テトラゾリウム化合物およびその化合物を用いる還元性物質の測定方法
JPS6445374U (cs) 1987-09-10 1989-03-20
DE3903993A1 (de) * 1989-02-10 1990-08-16 Basf Ag Diarylsubstituierte heterocyclische verbindungen, ihre herstellung und arzneimittel daraus
JPH04277724A (ja) * 1991-03-06 1992-10-02 Sumitomo Electric Ind Ltd 有機非線形光学材料
GB9113628D0 (en) * 1991-06-25 1991-08-14 Ici Plc Heterocyclic derivatives
US5219856A (en) * 1992-04-06 1993-06-15 E. I. Du Pont De Nemours And Company Angiotensin-II receptor blocking, heterocycle substituted imidazoles
US5334991A (en) 1992-05-15 1994-08-02 Reflection Technology Dual image head-mounted display
JPH05323522A (ja) * 1992-05-20 1993-12-07 Fuji Photo Film Co Ltd 黒白ハロゲン化銀写真感光材料の処理方法
US5604260A (en) * 1992-12-11 1997-02-18 Merck Frosst Canada Inc. 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
CA2152792C (en) * 1993-01-15 2000-02-15 Stephen R. Bertenshaw Novel 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents
US5409944A (en) * 1993-03-12 1995-04-25 Merck Frosst Canada, Inc. Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase
AU6718494A (en) * 1993-05-13 1994-12-12 Merck Frosst Canada Inc. 2-substituted-3,4-diarylthiophene derivatives as inhibitors of cyclooxygenase
US5434178A (en) 1993-11-30 1995-07-18 G.D. Searle & Co. 1,3,5 trisubstituted pyrazole compounds for treatment of inflammation
US5401765A (en) 1993-11-30 1995-03-28 G. D. Searle 1,4,5-triphenyl pyrazolyl compounds for the treatment of inflammation and inflammation-related disorders
US5393790A (en) * 1994-02-10 1995-02-28 G.D. Searle & Co. Substituted spiro compounds for the treatment of inflammation
US5486534A (en) 1994-07-21 1996-01-23 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
US5556019A (en) * 1994-07-25 1996-09-17 Sealed Air Corporation Bag separator and dispenser
JP3181190B2 (ja) * 1994-12-20 2001-07-03 日本たばこ産業株式会社 オキサゾール誘導体
JP2636819B2 (ja) * 1994-12-20 1997-07-30 日本たばこ産業株式会社 オキサゾール系複素環式芳香族化合物
US5633272A (en) * 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation
US5908858A (en) * 1996-04-05 1999-06-01 Sankyo Company, Limited 1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses
PT1288206E (pt) * 1996-04-12 2008-11-14 Searle Llc Derivados de benzenossulfonamida substituídos como pró-fármacos de inibidores de cox-2
JPH1045374A (ja) 1996-08-01 1998-02-17 Nittetsu Mining Co Ltd ドラム缶吊り上げ装置
US20030105144A1 (en) * 2001-04-17 2003-06-05 Ping Gao Stabilized oral pharmaceutical composition

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027980A1 (en) * 1993-05-21 1994-12-08 G.D. Searle & Co. Substituted oxazolyl compounds for the treatment of inflammation
WO1995000501A2 (en) * 1993-06-24 1995-01-05 Merck Frosst Canada Inc. Phenyl heterocycles as cyclooxygenase-2 inhibitors
US5344991A (en) * 1993-10-29 1994-09-06 G.D. Searle & Co. 1,2 diarylcyclopentenyl compounds for the treatment of inflammation
WO1995015316A1 (en) * 1993-11-30 1995-06-08 G. D. Searle & Co. Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
WO1995021817A1 (en) * 1994-02-10 1995-08-17 G.D. Searle & Co. Substituted spiro compounds for the treatment of inflammation
WO1996003388A1 (en) * 1994-07-28 1996-02-08 G.D. Searle & Co. 1,2-substituted imidazolyl compounds for the treatment of inflammation

Cited By (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0799823B1 (en) * 1996-04-05 2007-10-31 Daiichi Sankyo Company, Limited 1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses
US6586458B1 (en) 1996-08-16 2003-07-01 Pozen Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
US8022095B2 (en) 1996-08-16 2011-09-20 Pozen, Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
AU725697B2 (en) * 1997-04-03 2000-10-19 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of dementia
WO1998043648A1 (en) * 1997-04-03 1998-10-08 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of dementia
US7745481B2 (en) 1997-12-24 2010-06-29 Daiichi Sankyo Company, Limited Methods and compositions for the treatment and prevention of tumors, tumor-related disorders and cachexia
US6887893B1 (en) 1997-12-24 2005-05-03 Sankyo Company, Limited Methods and compositions for treatment and prevention of tumors, tumor-related disorders and cachexia
EP1061908A4 (en) * 1998-03-13 2007-01-24 Merck & Co Inc COMBINATION THERAPY AND COMPOSITION FOR ACUTE CORONARY MIXING SYNDROME AND ASSOCIATED CONDITIONS
US6395724B1 (en) 1998-06-08 2002-05-28 Advanced Medicine, Inc. Multibinding inhibitors of cyclooxygenase-2
WO2000029022A1 (en) * 1998-11-12 2000-05-25 Algos Pharmaceutical Corporation Cox-2 inhibitors in combination with centrally acting analgesics
WO2000048583A3 (en) * 1999-02-19 2000-12-07 Pozen Inc Formulation of 5-ht agonists with nsaids, especially cox-2 inhibitors, for treating migraine
US7432285B2 (en) 1999-12-23 2008-10-07 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US7166618B2 (en) 1999-12-23 2007-01-23 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US6649629B2 (en) 1999-12-23 2003-11-18 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US6878726B2 (en) 2000-03-03 2005-04-12 Pfizer Inc. Pyrazole ether derivatives as anti-inflammatory/analgesic agents
WO2001064669A1 (en) * 2000-03-03 2001-09-07 Pfizer Products Inc. Pyrazole ether derivatives as anti-inflammatory/analgesic agents
WO2001083475A1 (es) * 2000-04-25 2001-11-08 J. Uriach & Cia S.A. Nuevos compuestos heterociclicos con actividad antiinflamatoria
ES2166710A1 (es) * 2000-04-25 2003-12-01 Uriach & Cia Sa J Nuevos compuestos heterociclicos con actividad antiinflamatoria.
US6440963B1 (en) 2001-04-05 2002-08-27 Recordati S.A., Chemical And Pharmaceutical Company Use of selective COX-2 inhibitors for the treatment of urinary incontinence
US6613790B2 (en) 2001-04-17 2003-09-02 Pharmacia Corporation Prodrugs of COX-2 inhibitors
WO2002083655A1 (en) * 2001-04-17 2002-10-24 Pharmacia Corporation Prodrugs of cox-2 inhibitors
WO2003013655A3 (en) * 2001-08-10 2003-08-14 Pharmacia Corp Carbonic anhydrase inhibitors
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
US7211597B2 (en) 2001-09-19 2007-05-01 Suzanne Metz Substituted pyrazolyl compounds for the treatment of inflammation
WO2003024936A1 (en) * 2001-09-19 2003-03-27 Pharmacia Corporation Substituted pyrazolo compounds for the treatment of inflammation
US7482462B2 (en) 2001-10-05 2009-01-27 Amarylla Horvath Acylsulfonamides as inhibitors of steroid sulfatase
WO2003078408A1 (en) * 2002-03-15 2003-09-25 Pharmacia Corporation Crystalline parecoxib sodium
US7232821B2 (en) 2002-04-08 2007-06-19 Glaxo Group Limited (2-((2-alkoxy)-phenyl) -cyclopent-1enyl) aromatic carbo and heterocyclic acid and derivatives
US7442802B2 (en) 2002-06-27 2008-10-28 Nitromed, Inc. Cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7087630B2 (en) 2002-06-27 2006-08-08 Nitromed, Inc. Cyclooxygenase 2 selective inhibitors, compositions and methods of use
US7211598B2 (en) 2002-06-28 2007-05-01 Nitromed, Inc. Oxime and/or hydrozone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
EP1878725A2 (en) 2002-08-21 2008-01-16 Glaxo Group Limited Pyrimidine derivatives and their use as CB2 modulators
US7446222B2 (en) 2002-11-01 2008-11-04 Glaxo Group Limited Phenyl compounds
ES2215474A1 (es) * 2002-12-24 2004-10-01 J. URIACH & CIA S.A. Nuevos derivados de fosforamida.
US7550497B2 (en) 2002-12-24 2009-06-23 Palau Pharma, S.A. Phosphoramide derivatives
WO2004058778A1 (en) * 2002-12-24 2004-07-15 J. Uriach Y Compañia S.A. New phosphoramide derivatives
US7332183B2 (en) 2002-12-26 2008-02-19 Pozen Inc. Multilayer dosage forms containing NSAIDs and triptans
WO2004060367A1 (en) * 2002-12-30 2004-07-22 Fujisawa Pharmaceutical Co., Ltd. Imidazole and triazole derivatives useful as selective cox-1 inhibitors
WO2004087682A1 (en) * 2003-04-04 2004-10-14 Hetero Drugs Limited Novel crystalline forms of parecoxib sodium
WO2004092146A3 (en) * 2003-04-14 2004-12-29 Inst For Pharm Discovery Inc N- (((((1,3-thiazol-2-yl) amino) carbonyl) phenyl) sulfonyl) phenylalanine derivatives and related compounds for the treatment of diabetes
US7358364B2 (en) 2003-04-30 2008-04-15 The Institute For Pharmaceutical Discovery Llc Substituted carboxylic acids
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions
US7504519B2 (en) 2004-07-16 2009-03-17 Laboratorios Del Dr. Esteve, S.A. Derivatives of pyrazoline, procedure for obtaining them and use thereof as therapeutic agents
ES2257929B1 (es) * 2004-07-16 2007-05-01 Laboratorios Del Dr. Esteve, S.A. Derivados de pirazolina, procedimiento para su obtencion y utilizacion de los mismos como agentes terapeuticos.
JP2008506680A (ja) * 2004-07-16 2008-03-06 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ ピラゾリン誘導体、それを得るための方法および治療薬としてのその使用
WO2006011005A1 (en) * 2004-07-16 2006-02-02 Laboratorios Del Dr. Esteve, S.A. Derivatives of pyrazoline, procedure for obtaining them and use thereof as therapeutic agents
ES2257929A1 (es) * 2004-07-16 2006-08-01 Laboratorios Del Dr. Esteve, S.A. Derivados de pirazolina, procedimiento para su obtencion y utilizacion de los mismos como agentes terapeuticos.
EP2053042A1 (en) 2004-12-23 2009-04-29 Glaxo Group Limited Pyridine compounds for the treatment of prostaglandin mediated diseases
US7521435B2 (en) 2005-02-18 2009-04-21 Pharma Diagnostics, N.V. Silicon containing compounds having selective COX-2 inhibitory activity and methods of making and using the same
EA013232B1 (ru) * 2005-07-29 2010-04-30 Рихтер Гедеон Нирт. Новые 1,2-диарилпиразолы, пригодные в качестве болеутоляющих и противовоспалительных средств
WO2007012906A1 (en) * 2005-07-29 2007-02-01 Richter Gedeon Nyrt. New 1 , 2 -diaryl pyrazoles useful as analgetic and anti-inflammatory agents
US7470715B2 (en) 2005-12-22 2008-12-30 Pfizer Inc. Estrogen modulators
WO2008033931A1 (en) * 2006-09-13 2008-03-20 The Institutes For Pharmaceutical Discovery, Llc Para-xylylene carboxylic acids and isothiazolones useful as protein tyrosine phosphatases (ptps) in particular ptp-ib
WO2008093919A1 (en) * 2007-01-30 2008-08-07 Dongbu Hitek Co., Ltd. Use of n-benzyl-n-(2-dimethylamino-ethyl)benzenesulfonamide derivatives for treating central nervous system disorders
WO2008107455A1 (en) 2007-03-07 2008-09-12 Glaxo Group Limited Indazoles used to treat estrogen receptor beta mediated disorders
US7943658B2 (en) 2007-07-23 2011-05-17 Bristol-Myers Squibb Company Indole indane amide compounds useful as CB2 agonists and method
US8530478B2 (en) 2008-07-17 2013-09-10 Convergence Pharmaceuticals Limited Piperazine derivatives used as CAV2.2 calcium channel modulators
WO2010007074A1 (en) 2008-07-17 2010-01-21 Glaxo Group Limited Pyrazolo [1, 5-a] pyrimidine derivatives
US8598152B2 (en) 2008-10-17 2013-12-03 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibs
US9012440B2 (en) 2008-10-17 2015-04-21 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibs
US10238668B2 (en) 2008-10-17 2019-03-26 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibis
US10245276B2 (en) 2008-10-17 2019-04-02 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibs
US11478488B2 (en) 2008-10-17 2022-10-25 Esteve Pharmaceuticals, S.A. Co-crystals of tramadol and coxibs
US10548909B2 (en) 2008-10-17 2020-02-04 Esteve Pharmaceuticals, S.A. Co-crystals of tramadol and coxibs
WO2011012622A1 (en) 2009-07-30 2011-02-03 Glaxo Group Limited Benzoxazinone derivatives for the treatment of glytl mediated disorders
WO2011023753A1 (en) 2009-08-27 2011-03-03 Glaxo Group Limited Benzoxazine derivatives as glycine transport inhibitors
WO2011086377A1 (en) 2010-01-15 2011-07-21 Convergence Pharmaceuticals Limited PIPERAZINE DERIVATIVES FOR BLOCKING Cav2.2 CALCIUM CHANNELS
WO2011141729A1 (en) 2010-05-10 2011-11-17 Convergence Pharmaceuticals Limited Novel compounds
WO2011141728A1 (en) 2010-05-10 2011-11-17 Convergence Pharmaceuticals Limited Spirocyclic derivatives with affinity for calcium channels
US9750719B2 (en) 2010-07-09 2017-09-05 Convergence Pharmaceuticals Limited Tetrazole compounds as calcium channel blockers
US9115132B2 (en) 2010-07-09 2015-08-25 Convergence Pharmaceuticals Limited Tetrazole compounds as calcium channel blockers
WO2012004604A1 (en) 2010-07-09 2012-01-12 Convergence Pharmaceuticals Limited Tetrazole compounds as calcium channel blockers
CN103119039A (zh) * 2010-08-20 2013-05-22 阿勒根公司 作用于多种前列腺素受体以产生广泛抗炎反应的化合物
WO2012098400A1 (en) 2011-01-19 2012-07-26 Convergence Pharmaceuticals Limited Piperazine derivatives as cav2.2 calcium channel blockers
EP2780009A4 (en) * 2011-11-17 2015-05-06 Univ Colorado Regents METHOD AND COMPOSITIONS FOR IMPROVED DRUG RELEASE INTO EYE AND FORMULATIONS WITH EXTENDED RELEASE
US9562015B2 (en) 2011-11-17 2017-02-07 The Regents Of The University Of Colorado, A Body Methods and compositions for enhanced drug delivery to the eye and extended delivery formulations
WO2013093496A1 (en) 2011-12-22 2013-06-27 Convergence Pharmaceuticals Limited 2 - (pyridin- 2yl) - 1, 7 -diaza-spiro [4.4] nonane- 6 -one compound as voltage-gated sodium channels modulator
WO2013093497A1 (en) 2011-12-22 2013-06-27 Convergence Pharmaceuticals Limited 2 - (pyridin- 2yl) - 1, 7 -diaza- spiro [4.4] nonane- 6 -one compounds as voltage - gated sodium channels modulators
WO2016051194A1 (en) 2014-10-03 2016-04-07 Convergence Pharmaceuticals Limited Erythromelalgia treatment
WO2016051196A1 (en) 2014-10-03 2016-04-07 Convergence Pharmaceuticals Limited Paroxysmal extreme pain disorder treatment
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US10493059B2 (en) 2014-10-03 2019-12-03 Convergence Pharmaceuticals Limited Paroxysmal extreme pain disorder treatment
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WO2022195579A1 (en) 2021-03-15 2022-09-22 Saul Yedgar Hyaluronic acid-conjugated dipalmitoyl phosphatidyl ethanolamine in combination with non-steroidal anti-inflammatory drugs (nsaids) for treating or alleviating inflammatory diseases

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